Low Lp Research Articles

Causal associations of insulin and Lp(a) levels: a Mendelian randomization study

Abstract Background Numerous observational studies have demonstrated circulating lipoprotein(a) [Lp(a)] to be inversely related to occurrence of type 2 diabetes [T2D]. However, this is not consistently supported by Mendelian randomization [MR] studies. In vitro studies have shown insulin to downregulate Lp(a) expression, which might be another mechanism behind the correlation observed between Lp(a) and T2D. Purpose In this MR study, we investigated the influence of genetically predicted levels of insulin on genetically predicted Lp(a) levels to elucidate the potential causal links between Lp(a) and diabetes. Methods Independent genetic variants associated with insulin levels were acquired from a meta-analysis of genome-wide association studies (GWAS, N=151,013). Summary data for Lp(a) were acquired from a GWAS study in the UK Biobank (N=361,194). Inverse-variance-weighted (IVM) method was used to perform a two sample MR study. Sensitivity analysis was conducted via MR Egger, weighted median (WME), as well as leave-one-out analysis. Results Genetically predicted insulin levels were negatively associated with Lp(a) levels according to IVM estimate (p=0.003). In sensitivity analysis, WME supported this result (p=0.0002), while MR-Egger was not statistically significant (p=0.11). Leave-one-out analysis did not show the results to depend on any single variant. Conclusion This MR study provides robust evidence supporting the association between plasma insulin levels and decreased Lp(a) concentration. These findings suggest that hyperinsulinemia triggered by insulin resistance can be in part responsible for the observed negative correlation between low Lp(a) and T2D risk. Figure 1. Genetic associations between insulin levels and Lp(a). Each genetic variant included in the analysis is represented as a point + 95% CI. Localization on the horizontal axis represents the correlation of the variant with exposure (plasma fasting insulin, inverse variance normal transformed values). Localization on the vertical axis represents the correlation of the variant with outcome (Lp(a), natural log transformed values). Lines represent estimates of different MR methods.Figure 1.

Impact of High Lipoprotein(a) Levels on Delayed Wound Healing in Patients With Chronic Limb-Threatening Ischemia After Peripheral Endovascular Therapy.

Elevated lipoprotein(a) [Lp(a)] levels are a causal risk factor for peripheral artery disease. However, data on their effect on delayed wound healing in patients with chronic limb-threatening ischemia (CLTI) are limited. The present study assessed the association between elevated Lp(a) levels and delayed wound healing in patients with CLTI. This study included 280 patients who successfully received endovascular therapy for CLTI between September 2016 and August 2021. High Lp(a) levels were defined as those >30 mg/dL. The primary outcome was wound healing. During a median follow-up of 20.4 months (interquartile range 6.8-38.6 months), 146 patients achieved wound healing. The wound healing rate at 24 months was significantly lower in the high Lp(a) than low Lp(a) group (41.1% vs. 86.3%, respectively; P<0.001). The adjusted risk ratio was 0.19 (95% confidence interval 0.13-0.29, P<0.001). Lp(a) levels of 31-50 and >50 mg/dL, but not 16-30 mg/dL, were significantly associated with delayed wound healing relative to Lp(a) levels of ≤15 mg/dL. Elevated Lp(a) levels were independently associated with delayed wound healing in patients with CLTI treated with endovascular therapy.

Hierarchical porous ACNF/MIL-68(In)–NH2 composites for rapid and efficient removal of losartan from water: Unveiling adsorption mechanisms and superior performance

Losartan (LP), a medication commonly used to treat hypertension, has emerged as a potential environmental pollutant. Despite its widespread use, research on the efficient and rapid removal of LP from the environment remains very scarce. The limited studies on LP adsorption indicate that the adsorption capacity and rate of LP need improvement. In this study, we successfully prepared a hierarchical porous nitric acid-treated carbon nanofiber (ACNF)/MIL-68(In)–NH2 composite with a robust three-dimensional support structure using a simple hydrothermal method for the first time to adsorb LP. The resulting ACNF/MIL-68(In)–NH2 composite demonstrated exceptional adsorption capabilities, achieving an equilibrium absorption capacity of 259.87 mg/g within just 64 min, significantly outperforming previously reported results. Langmuir fitting indicated a maximum theoretical adsorption capacity exceeding 630 mg/g at 55 °C. For actual wastewater with low LP concentrations, complete removal was achieved with a minimal dose of the ACNF/MIL-68(In)–NH2 adsorbent. DFT calculations and Multiwfn wavefunction analysis revealed that the adsorption behavior of LP onto ACNF/MIL-68(In)–NH2 is primarily driven by electrostatic interactions, multiple hydrogen bonds, π-π stacking interactions, and van der Waals forces. This work presents an innovative strategy for the efficient and rapid removal of residual LP from water environments.

Causal associations between insulin and Lp(a) levels in Caucasian population: a Mendelian randomization study

BackgroundNumerous observational studies have demonstrated that circulating lipoprotein(a) [Lp(a)] might be inversely related to the risk of type 2 diabetes (T2D). However, recent Mendelian randomization (MR) studies do not consistently support this association. The results of in vitro research suggest that high insulin concentrations can suppress Lp(a) levels by affecting apolipoprotein(a) [apo(a)] synthesis. This study aimed to identify the relationship between genetically predicted insulin concentrations and Lp(a) levels, which may partly explain the associations between low Lp(a) levels and increased risk of T2D.MethodsIndependent genetic variants strongly associated with fasting insulin levels were identified from meta-analyses of genome-wide association studies in European populations (GWASs) (N = 151,013). Summary level data for Lp(a) in the population of European ancestry were acquired from a GWAS in the UK Biobank (N = 361,194). The inverse-variance weighted (IVW) method approach was applied to perform two-sample summary-level MR. Robust methods for sensitivity analysis were utilized, such as MR‒Egger, the weighted median (WME) method, MR pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out analysis, and MR Steiger.ResultsGenetically predicted fasting insulin levels were negatively associated with Lp(a) levels (β = − 0.15, SE = 0.05, P = 0.003). The sensitivity analysis revealed that WME (β = − 0.26, SE = 0.07, P = 0.0002), but not MR‒Egger (β = − 0.22, SE = 0.13, P = 0.11), supported a causal relationship between genetically predisposed insulin levels and Lp(a).ConclusionOur MR study provides robust evidence supporting the association between genetically predicted increased insulin concentrations and decreased concentrations of Lp(a). These findings suggest that hyperinsulinaemia, which typically accompanies T2D, can partially explain the inverse relationship between low Lp(a) concentrations and an increased risk of T2D.

Spatial analysis and characteristics of persistent late potentials after ablation of scar-related VT substrate: Implications for late potential elimination as a procedural endpoint with high-resolution mapping

BackgroundLate potential (LP) elimination has been proposed as a surrogate endpoint for scar-related ventricular tachycardia (VT) ablation procedures. The characteristics, distribution, and predictors of persistent late potentials (pLPs) after ablation have not been studied. ObjectiveThe purpose of this study was to characterize the spatial distribution and features of pLP after catheter ablation of VT substrate with high-resolution mapping. MethodsCases of scar-related VT ablation with adequate pre- and postablation electroanatomic maps (EAMs) acquired exclusively using a high-density grid catheter were reviewed from 2021 to 2023. ResultsA total of 62 EAMs (pre- and postablation) from 31 cases using a high-density grid catheter were reviewed. pLPs were observed in 19 cases (61%) after ablation. New LP, spatially distinct from preablation LP, at the periphery of the ablation area comprised the majority of pLPs (16/19 [84%]). Isolated pLPs were more prevalent than fractionated pLPs, with a median amplitude of 0.26 mV (0.09–0.59 mV). The presence of pLP was associated with a significantly lower left ventricular ejection fraction (LVEF) and septal ablation but not low voltage, LP, or ablation area compared to absence of pLP (22.8% ± 7.8% vs 31.5% ± 8.0%, P = .008 for LVEF; 83% vs 44%, P = .033 for septal ablation). ConclusionFormation of spatially distinct new LP after targeted VT ablation is common, especially in patients with lower LVEF and septal substrate independent of ablation burden. This finding highlights the limitations of complete LP elimination as an endpoint to VT ablation procedures.

A Polynesian-specific SLC22A3 variant associates with low plasma lipoprotein(a) concentrations independent of apo(a) isoform size in males.

Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL)-like particle in which the apolipoprotein B component is covalently linked to apolipoprotein(a) (apo(a)). Lp(a) is a well-established independent risk factor for cardiovascular diseases. Plasma Lp(a) concentrations vary enormously between individuals and ethnic groups. Several nucleotide polymorphisms in the SLC22A3 gene associate with Lp(a) concentration in people of different ethnicities. We investigated the association of a Polynesian-specific (Māori and Pacific peoples) SLC22A3 gene coding variant p.Thr44Met) with the plasma concentration of Lp(a) in a cohort of 302 healthy Polynesian males. An apo(a)-size independent assay assessed plasma Lp(a) concentrations; all other lipid and apolipoprotein concentrations were measured using standard laboratory techniques. Quantitative real-time polymerase chain reaction was used to determine apo(a) isoforms. The range of metabolic (HbA1c, blood pressure, and blood lipids) and blood lipid variables were similar between the non-carriers and carriers in age, ethnicity and BMI adjusted models. However, rs8187715 SLC22A3 variant was significantly associated with lower Lp(a) concentrations. Median Lp(a) concentration was 10.60 nmol/L (IQR: 5.40-41.00) in non-carrier group, and was 7.60 nmol/L (IQR: 5.50-12.10) in variant carrier group (P<0.05). Lp(a) concentration inversely correlated with apo(a) isoform size. After correction for apo(a) isoform size, metabolic parameters and ethnicity, the association between the SLC22A3 variant and plasma Lp(a) concentration remained. The present study is the first to identify the association of this gene variant and low plasma Lp(a) concentrations. This provides evidence for better guidance on ethnic specific cut-offs when defining 'elevated' and 'normal' plasma Lp(a) concentrations in clinical applications.

Associations of very low Lipoprotein(a) levels with risks of new-onset diabetes and non-alcoholic liver disease

Background and aimsWe aimed to study the association of very low serum Lipoprotein(a) [Lp(a)] concentrations with new-onset type 2 diabetes (T2D) and non-alcoholic liver disease (NAFLD) in the context of statin usage in the UK Biobank, a large prospective population cohort. MethodsUsing an extended biomarker dataset, we identified 47,362 participants with very low Lp(a) concentrations (<3.8 nmol/L) from a total of 451,479 participants. With a median follow-up of 12.3 years, we assessed the risk of new-onset cardiometabolic diseases in participants stratified by statin usage with Cox proportional hazards models. We performed two-sample Mendelian randomization MR analyses to test causal relationship between genetically predicted Lp(a) and T2D and NAFLD. ResultsTaking the participants with Lp(a) within reportable range as the reference group, the hazard ratios (HR) for T2D were 1.07 (95 % confidence interval, CI 1.01–1.13) and for NAFLD 1.30 (95 % CI 1.20–1.41) respectively for participants with very low Lp(a) (<3.8 nmol/L). The risk for new-onset T2D was higher in participants using statins (adjusted HR 1.15; 95 % CI 1.05–1.27). The risk estimates for new-onset NAFLD were comparable in the analysis stratified by statin use. There was no evidence for causal links between genetically predicted Lp(a) and T2D nor NAFLD in two-sample MR analyses. ConclusionsVery low Lp(a) was associated with higher risks of T2D and NAFLD in a prospective analysis of the UK Biobank. The association with T2D was influenced by lipid lowering medication usage. MR analyses did not support causality for these inverse associations.

Lipoprotein(a) and long-term in-stent restenosis after percutaneous coronary intervention.

Lipoprotein(a) [Lp(a)] has demonstrated its association with atherosclerosis and myocardial infarction. However, its role in the development of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is not clearly established. The aim of this study is to investigate the association between Lp(a) and ISR. A retrospective study of adult patients who underwent successful PCI between January 2006 and December 2017 at the three Mayo Clinic sites and had a preprocedural Lp(a) measurement was conducted. Patients were divided into two groups according to the serum Lp(a) concentration [high Lp(a) ≥ 50 mg/dL and low Lp(a) < 50 mg/dL]. Univariable and multivariable analyses were performed to compare risk of ISR between patients with high Lp(a) vs. those with low Lp(a). A total of 1209 patients were included, with mean age 65.9 ± 11.7 years and 71.8% were male. Median follow-up after baseline PCI was 8.8 [interquartile range (IQR) 7.4] years. Restenosis was observed in 162 (13.4%) patients. Median serum levels of Lp(a) were significantly higher in patients affected by ISR vs. non-affected cases: 27 (IQR 73.8) vs. 20 (IQR 57.5) mg/dL, P = 0.008. The rate of ISR was significantly higher among patients with high Lp(a) vs. patients with low Lp(a) values (17.0% vs. 11.6%, P = 0.010). High Lp(a) values were independently associated with ISR events (hazard ratio 1.67, 95% confidence interval 1.18-2.37, P = 0.004), and this association was more prominent after the first year following the PCI. Lipoprotein(a) is an independent predictor for long-term ISR and should be considered in the evaluation of patients undergoing PCI.

Association between lipoprotein levels and outcomes after coronary artery bypass grafting surgery: a systematic review and meta-analysis.

Lipoprotein(a) (Lp[a]) is a variant of low-density lipoprotein (LDL) and has been associated with increased risk of vascular inflammation and thrombosis. Coronary artery bypass grafting (CABG) has been associated with local inflammation of the myocardium. It is plausible, therefore, that patients with elevated baseline Lp(a) may be prone to unfavorable clinical outcomes following CABG. We evaluate differences in outcomes between CABG patients with high and low serum Lp(a) in this meta-analysis. A comprehensive literature search was performed to identify studies reporting outcomes in CABG patients stratified by preoperative Lp(a) level. When possible, the outcomes were pooled in a meta-analysis. We assessed post-operative mortality, major cardiovascular events, stroke occurrence and saphenous graft occlusion. Eight studies involving 8681 patients were included. Articles used varying cut-offs for high versus low Lp(a), and outcomes varied. In the three studies evaluating mortality, two showed no statistically significant difference between groups while one reported increased mortality associated with high Lp(a) level. Both studies investigating major adverse cardiovascular events reported higher risk in patients with high Lp(a). A study-level meta-analysis of four studies reporting saphenous vein graft occlusion incidence after CABG was performed. High (≥30 mg/dL) preoperative Lp(a) was not associated with an increased risk of graft occlusion compared with low (<30 mg/dL) preoperative Lp(a) (OR=1.88, 95% CI: 0.66-5.36; P=0.15). Studies evaluating the impact of Lp(a) on outcomes in CABG patients are few, with heterogenous cut-offs and outcomes. In the limited published studies, Lp(a) level was not associated with graft occlusion.

Association of Lipoprotein (a) and Standard Modifiable Cardiovascular Risk Factors With Incident Myocardial Infarction: The Mass General Brigham Lp(a) Registry.

Lipoprotein (a) [Lp(a)] is a robust predictor of coronary heart disease outcomes, with targeted therapies currently under investigation. We aimed to evaluate the association of high Lp(a) with standard modifiable risk factors (SMuRFs) for incident first acute myocardial infarction (AMI). This retrospective study used the Mass General Brigham Lp(a) Registry, which included patients aged ≥18 years with an Lp(a) measurement between 2000 and 2019. Exclusion criteria were severe kidney dysfunction, malignant neoplasm, and prior known atherosclerotic cardiovascular disease. Diabetes, dyslipidemia, hypertension, and smoking were considered SMuRFs. High Lp(a) was defined as >90th percentile, and low Lp(a) was defined as <50th percentile. The primary outcome was fatal or nonfatal AMI. A combination of natural language processing algorithms, International Classification of Diseases (ICD) codes, and laboratory data was used to identify the outcome and covariates. A total of 6238 patients met the eligibility criteria. The median age was 54 (interquartile range, 43-65) years, and 45% were women. Overall, 23.7% had no SMuRFs, and 17.8% had ≥3 SMuRFs. Over a median follow-up of 8.8 (interquartile range, 4.2-12.8) years, the incidence of AMI increased gradually, with higher number of SMuRFs among patients with high (log-rank P=0.031) and low Lp(a) (log-rank P<0.001). Across all SMuRF subgroups, the incidence of AMI was significantly higher for patients with high Lp(a) versus low Lp(a). The risk of high Lp(a) was similar to having 2 SMuRFs. Following adjustment for confounders and number of SMuRFs, high Lp(a) remained significantly associated with the primary outcome (hazard ratio, 2.9 [95% CI, 2.0-4.3]; P<0.001). Among patients with no prior atherosclerotic cardiovascular disease, high Lp(a) is associated with significantly higher risk for first AMI regardless of the number of SMuRFs.

Elevated Plasma Lipoprotein(a) Level and Atherosclerotic Cardiovascular Disease Risks: A Large Clinical Retrospective Study.

Patients with well-controlled low-density lipoprotein cholesterol (LDL-C) levels still suffer from the progress of the atherosclerotic cardiovascular disease (ASCVD) and can develop adverse outcomes. We conducted this study to analyze the relationship between elevated lipoprotein(a) [Lp(a)] levels and ASCVD risk. We enrolled 8070 patients in the ASCVD group and 440 participants in the non-ASCVD group [median age of 60years; 6376 (74.9%) were male]. Multivariate logistic regression models were used to identify the relationships between the lipids and ASCVD. These models showed that the Lp(a) level was a significant independent risk factor for ASCVD [odds ratio (OR) = 1.025, confidence interval (CI) = 1.020-1.029, P < .001]. The different categories analysis showed the OR of the high Lp(a)/low LDL-C group was 9.612 [CI = 6.206-14.887], P < .001. Our study demonstrated that elevated Lp(a) levels were associated with the increased ASCVD risk. Also, the patients with low LDL-C but high Lp(a) levels still had a higher risk of developing ASCVD than the low Lp(a)/high LDL-C group. In addition, elevated Lp(a) levels were associated with a higher ASCVD risk in males, hypertensive, and diabetic patients.

Relationship Between Lipoprotein(a), Renal Function Indicators, and Chronic Kidney Disease: Evidence From a Large Prospective Cohort Study.

Chronic kidney disease (CKD) poses a significant global public health challenge. While lipoprotein(a) (Lp[a]) has been established as a significant factor in cardiovascular disease, its connection to CKD risk remains a topic of debate. Existing evidence indicates diverse risks of kidney disease among individuals with various renal function indicators, even when within the normal range. This study aims to investigate the joint associations between different renal function indicators and Lp(a) regarding the risks of incident CKD in the general population. The analysis involved a cohort of 329,415 participants without prior CKD who were enrolled in the UK Biobank between 2006 and 2010. The participants, with an average age of 56 (SD 8.1) years, included 154,298/329,415 (46.84%) males. At baseline, Lp(a) levels were measured using an immunoturbidimetric assay and classified into 2 groups: low (<75 nmol/L) and high (≥75 nmol/L). To assess participants' baseline renal function, we used the baseline urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The relationship between Lp(a), renal function indicators, and the risk of CKD was evaluated using multivariable Cox regression models. These models were adjusted for various factors, including sociodemographic variables, lifestyle factors, comorbidities, and laboratory measures. A total of 6003 incident CKD events were documented over a median follow-up period of 12.5 years. The association between elevated Lp(a) levels and CKD risk did not achieve statistical significance among all participants, with a hazard ratio (HR) of 1.05 and a 95% CI ranging from 0.98 to 1.13 (P=.16). However, a notable interaction was identified between Lp(a) and UACR in relation to CKD risk (P for interaction=.04), whereas no significant interaction was observed between Lp(a) and eGFR (P for interaction=.96). When compared with the reference group with low Lp(a) and low-normal UACR (<10 mg/g), the group with high Lp(a) and low-normal UACR exhibited a nonsignificant association with CKD risk (HR 0.98, 95% CI 0.90-1.08; P=.74). By contrast, both the low Lp(a) and high-normal UACR (≥10 mg/g) group (HR 1.16, 95% CI 1.08-1.24; P<.001) and the high Lp(a) and high-normal UACR group (HR 1.32, 95% CI 1.19-1.46; P<.001) demonstrated significant associations with increased CKD risks. In individuals with high-normal UACR, elevated Lp(a) was linked to a significant increase in CKD risk, with an HR of 1.14 and a 95% CI ranging from 1.03 to 1.26 (P=.01). Subgroup analyses and sensitivity analyses consistently produced results that were largely in line with the main findings. The analysis revealed a significant interaction between Lp(a) and UACR in relation to CKD risk. This implies that Lp(a) may act as a risk factor for CKD even when considering UACR. Our findings have the potential to provide valuable insights into the assessment and prevention of CKD, emphasizing the combined impact of Lp(a) and UACR from a public health perspective within the general population. This could contribute to enhancing public awareness regarding the management of Lp(a) for the prevention of CKD.

Diacylglycerols and Lysophosphatidic Acid, Enriched on Lipoprotein(a), Contribute to Monocyte Inflammation.

Oxidized phospholipids play a key role in the atherogenic potential of lipoprotein(a) (Lp[a]); however, Lp(a) is a complex particle that warrants research into additional proinflammatory mediators. We hypothesized that additional Lp(a)-associated lipids contribute to the atherogenicity of Lp(a). Untargeted lipidomics was performed on plasma and isolated lipoprotein fractions. The atherogenicity of the observed Lp(a)-associated lipids was tested ex vivo in primary human monocytes by RNA sequencing, ELISA, Western blot, and transendothelial migratory assays. Using immunofluorescence staining and single-cell RNA sequencing, the phenotype of macrophages was investigated in human atherosclerotic lesions. Compared with healthy individuals with low/normal Lp(a) levels (median, 7 mg/dL [18 nmol/L]; n=13), individuals with elevated Lp(a) levels (median, 87 mg/dL [218 nmol/L]; n=12) demonstrated an increase in lipid species, particularly diacylglycerols (DGs) and lysophosphatidic acid (LPA). DG and the LPA precursor lysophosphatidylcholine were enriched in the Lp(a) fraction. Ex vivo stimulation with DG(40:6) demonstrated a significant upregulation in proinflammatory pathways related to leukocyte migration, chemotaxis, NF-κB (nuclear factor kappa B) signaling, and cytokine production. Functional assessment showed a dose-dependent increase in the secretion of IL (interleukin)-6, IL-8, and IL-1β after DG(40:6) and DG(38:4) stimulation, which was, in part, mediated via the NLRP3 (NOD [nucleotide-binding oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome. Conversely, LPA-stimulated monocytes did not exhibit an inflammatory phenotype. Furthermore, activation of monocytes by DGs and LPA increased their transendothelial migratory capacity. Human atherosclerotic plaques from patients with high Lp(a) levels demonstrated colocalization of Lp(a) with M1 macrophages, and an enrichment of CD68+IL-18+TLR4+ (toll-like receptor) TREM2+ (triggering receptor expressed on myeloid cells) resident macrophages and CD68+CASP1+ (caspase) IL-1B+SELL+ (selectin L) inflammatory macrophages compared with patients with low Lp(a). Finally, potent Lp(a)-lowering treatment (pelacarsen) resulted in a reduction in specific circulating DG lipid subspecies in patients with cardiovascular disease with elevated Lp(a) levels (median, 82 mg/dL [205 nmol/L]). Lp(a)-associated DGs and LPA have a potential role in Lp(a)-induced monocyte inflammation by increasing cytokine secretion and monocyte transendothelial migration. This DG-induced inflammation is, in part, NLRP3 inflammasome dependent.

Genetic variability of lipoprotein(a) controls vascular inflammation/redox signalling and predicts adverse cardiovascular outcomes in coronary artery disease

Abstract Introduction Lipoprotein(a) [Lp(a)] has an established link with cardiovascular disease, however the underlying mechanisms are incompletely understood. Objective We investigate the prognostic value of LPA genetic variants that determine Lp(a) levels, in patients with coronary artery disease. Methods We determined the plasma Lp(a) levels of 1472 cardiac surgery patients and performed genotyping to identify 7 SNPs in LPA that are associated with increased Lp(a) levels. We compared subjects with alternative LPA alleles from ≥3 SNPs (alternative group) to those without (reference group). The arterial redox state of internal mammary artery (IMA) samples was quantified using lucigenin chemiluminescence and nicotinamide adenine dinucleotide phosphate (NADPH). Coronary inflammation was measured using coronary CT angiography (CCTA) by applying Perivascular Fat Attenuation Indexing (FAI) in the proximal left anterior descending (LAD) coronary artery. To best describe cytokine-driven vascular inflammation, a radiotranscriptomic signature (C19RS) derived from the perivascular space around the aorta and the IMA was used. Patients were followed up for a median of 7.8 years. Results Patients with high plasma Lp(a) levels, those in the top third of the population, had significantly increased arterial NADPH-stimulated O2.- (A) compared to those with medium or low plasma Lp(a) levels. Amongst patients with high plasma Lp(a): those with Lp(a) levels ≥75th percentile (compared to those below) had a significantly increased perivascular FAI (B), and those with Lp(a) levels ≥95th percentile (compared to those below) had a significantly increased C19RS (C). Images of CCTA FAI mapping of LADs from alternative and reference LPA variant group patients are shown (D). Amongst insulin-sensitive patients with high plasma Lp(a), those in the alternative LPA variant group (vs the reference group) had significantly increased plasma Lp(a) levels (p&amp;lt;0.001), plasma apolipoprotein-B (ApoB) levels (p=0.025), resting arterial O2.- levels (E), and C19RS (F). There was a significantly increased observed risk of major adverse cardiovascular events, independent of plasma ApoB, for patients with high plasma Lp(a) levels (adj. HR=2.664, p=0.022) as well as for those in the alternative LPA variant group (adj. HR=2.018, p=0.049). IMA RNAseq pathway enrichment analyses revealed that, in patients with plasma Lp(a) levels ≥95th percentile, there was a significant upregulation of genes involved in the mitochondrial electron transport chain, reactive oxygen species response and positive regulation of lymphocyte chemotaxis. Conclusions We demonstrate for the first time that Lp(a) leads to increased coronary inflammation in humans, which could mediate the increased risk of major adverse cardiovascular events associated with high Lp(a) levels.

Abstract 16773: The Association of Lp(a) and Standard Modifiable Cardiovascular Risk Factors (SMuRFs) With Incident Myocardial Infarction: The Mass General Brigham Lp(a) Registry

Introduction: Lp(a) is a robust predictor of coronary heart disease outcomes, with targeted therapies currently under investigation. However, there is a paucity of data regarding the risk of elevated Lp(a) in relation to other cardiovascular risk factors. Objective: To evaluate the association of high Lp(a) with standard modifiable risk factors (SMuRFs) for incident first acute myocardial infarction (AMI). Methods: This retrospective study utilized the MGB Lp(a) Registry which included patients ≥18 years with an Lp(a) measurement between 2000-2019. Exclusion criteria were severe kidney dysfunction, malignant neoplasm, and prior known atherosclerotic cardiovascular disease (ASCVD). Diabetes mellitus, hyperlipidemia, hypertension, and smoking were considered SMuRFs. High Lp(a) was defined as &gt;90 th percentile and low Lp(a) as &lt;50 th . The primary outcome was fatal or non-fatal AMI. A combination of natural language processing algorithms, ICD codes, and laboratory data were employed to identify the outcome and covariates. Results: A total of 6,238 patients met the eligibility criteria. The median age was 54 (IQR: 43-65) years and 45% were women. Overall, 23.7% had no SMuRFs and 17.8% had ≥3 SMuRFs. Over a median follow-up of 8.8 (IQR: 4.2-12.8) years, the incidence of AMI increased in a stepwise manner with higher number of SMuRFs among patients with high (logrank p=0.031) and low Lp(a) (logrank p&lt;0.001). Across all SMuRFs subgroups, the incidence of AMI was significantly higher for patients with high Lp(a) vs. low Lp(a) (Figure 1). The risk of high Lp(a) was higher than the risk imposed by any of the SMuRFs and was similar to having two SMuRFs. Following adjustment for confounders and number of SMuRFs, high Lp(a) remained independently associated with the primary outcome (HR=2.9 (95%CI=2.0-4.3), p&lt;0.001). Conclusions: Among patients with no prior ASCVD, high Lp(a) is independently associated with increased risk for first AMI regardless of the number of SMuRFs.

Abstract 15072: Lipoprotein(a) Regulates Vascular Redox State and Predicts Adverse Cardiovascular Outcomes in Coronary Artery Disease

Introduction: Lipoprotein(a) [Lp(a)] has an established link with cardiovascular disease yet the underlying mechanisms are incompletely understood. Methods: In 1472 cardiac surgery patients, we compared patients with any alternative allele from ≥3 of 7 Lp(a)-increasing SNPs (alternative variant group) to those with no alternative alleles in any of these SNPs (reference variant group). Plasma Lp(a) was measured using the Randox assay. The arterial redox state was measured using lucigenin chemiluminescence, where the contribution of NADPH-oxidases (NOX) and uncoupled nitric oxide synthases (eNOS) to superoxide (O 2 .- ) production was quantified. Arterial biopsies were used to perform RNA-sequencing. Patients were followed up for a median of 7.8 years. Results: Alternative variant patients had significantly higher plasma Lp(a) (A), plasma apolipoprotein-B (ApoB) (p&lt;0.01), and arterial basal-O 2 .- (B). Patients with medium/high vs low plasma Lp(a) had significantly increased plasma ApoB (p&lt;0.0001) and arterial basal-O 2 .- (C) as well as reduced tetrahydrobiopterin bioavailability (p&lt;0.01). The association between Lp(a) and arterial basal-O 2 .- was ApoB-independent. Non-diabetic patients in the alternative variant group and those with medium/high plasma Lp(a) had significantly increased arterial basal and eNOS-derived (p&lt;0.05), but not NOX-derived, O 2 .- . The transcriptomic profile of patients with high vs low plasma Lp(a) showed significantly downregulated PI3K-Akt signalling (D). Genetic tools revealed that Lp(a) is causally associated with an increased risk of cardiovascular death in an ApoB-independent manner (E). Patients with medium/high plasma Lp(a) also had a significantly increased risk of cardiovascular death (adj. HR=4.274 [95%CI: 1.227, 14.925], p=0.022). Conclusions: We demonstrate that Lp(a) increases arterial O 2 .- through dysregulating vascular insulin signalling, mediating its association with cardiovascular disease.

Abstract 18432: Lipoprotein(a) is Associated With Long-Term Plaque Progression, Pericoronary Inflammation and High-Risk Plaque on Serial Coronary CT Angiography

Background This study investigated the effect of lipoprotein(a) (Lp[a]) on long-term plaque progression, high-risk plaque (HRP) and pericoronary adipose tissue attenuation (PCATa) in patients suspected of coronary artery disease. Methods: Per-protocol, patients from a coronary CT angiography (CCTA) cohort (Diemen et al., 2021) were invited for repeat CCTA imaging, regardless of symptoms. A total of 299 patients underwent follow-up CCTA imaging with a median scan interval of 10.2 [IQR 8.7-11.2] years. Patients who underwent coronary artery bypass grafting and vessels revascularized by percutaneous coronary intervention were excluded. Scans were analyzed using atherosclerosis-imaging quantitative CCTA (AI-QCT; Cleerly Inc.). The associations between high (Tertile 3; &gt;67 nmol/l) and low Lp(a) (Tertile 1 and 2; ≤67 nmol/l), baseline and follow-up plaque burden and characteristics were evaluated using multivariable regression adjusted for clinical risk factors, statin use and scanner settings. Results: In total, 274 patients were included, mean age was 57±7 years, 42% were women. Patients with high Lp(a) levels had higher volumes of percent atheroma volume (PAV) at baseline and follow-up and higher rate of plaque progression (Figure 1A). The difference in PAV caused by high Lp(a) versus low Lp(a) patients was similar to the effect of a 12-year age difference. At baseline, patients in the highest tertile of Lp(a) levels had a higher prevalence of both HRP (OR 2.24; p=0.009) and above-median right coronary artery PCATa (OR 1.76; p=0.049). Finally, patients with high Lp(a) levels had a twofold higher incidence of major adverse cardiovascular events (MACE; Figure 1B; p=0.044). Conclusion: Patients with high Lp(a) levels had increased coronary plaque burden, increased prevalence of high-risk plaque and pericoronary inflammation as well as increased plaque progression leading to an increased incidence of MACE throughout 10-year follow-up.

Lack of association between Lp(a) and retinal vein occlusion in a single institution and US national database

ObjectifCette étude se penche sur l'association entre la lipoprotéine (a) (Lp[a]), lipoprotéine apparentée aux lipoprotéines de basse densité, et l'occlusion veineuse rétinienne (OVR) dans des cohortes américaines afin de déterminer son rôle quant au pronostic de l'OVR. NatureÉtude de cohorte rétrospective en 2 phases. MéthodesPendant la première phase, on a passé en revue les dossiers des patients d'un centre unique de soins tertiaires qui avaient une OVR et pour lesquels on disposait d'une mesure quantitative du taux de Lp(a). On a ensuite évalué le taux de Lp(a) en association avec différentes caractéristiques, dont l’âge au moment du diagnostic d'OVR, l'acuité visuelle, le temps écoulé avant l'apparition de l'OVR et l’épaisseur du sous-champ central. Au cours de la deuxième phase, on a vérifié dans TriNetX US Collaborative Network, importante base de données nationale, la présence de taux élevés ou faibles de Lp(a) en association à un diagnostic d'OVR. RésultatsNous avons repéré, dans notre centre de soins tertiaires, 45 porteurs d'une OVR pour lesquels on disposait du taux de Lp(a). Aucune association significative n'a été découverte entre le taux de Lp(a) et l’âge au moment de l'apparition de l'OVR, le temps écoulé entre le prélèvement et l'apparition de l'OVR, l'acuité visuelle et l’épaisseur du sous-champ central (p > 0,05 pour l'ensemble des mesures). La base de données nationale TriNetX a fait ressortir 35 687 patients chez lesquels le taux de Lp(a) était élevé (> 30 mg/dL ou 61 nmol/L) et 51 692 patients chez lesquels le taux de Lp(a) était faible. Un taux élevé de Lp(a) n’était pas associé à une plus forte probabilité d'occlusion de la veine rétinienne centrale (rapport de cotes [RC] = 1,15; intervalle de confiance [IC] à 95 % : 0,88–1,50) ni d'occlusion d'une branche veineuse rétinienne (RC = 1,01; IC à 95 % : 0,76–1,36). ConclusionLes 2 phases de notre analyse permettent de conclure à l'absence de lien entre le taux de Lp(a) et le risque d'OVR. Voilà qui souligne l'importance des grandes bases de données nationales quand vient le temps de valider les résultats de laboratoire que des études d'observation de petite envergure avaient retenus à titre de facteurs prédictifs.

Contribution of Lipoprotein(a) to Polygenic Risk Prediction of Coronary Artery Disease: A Prospective UK Biobank Analysis.

Lp(a) (lipoprotein[a]) is a highly atherogenic lipoprotein subfraction that may contribute to polygenic risk of coronary artery disease (CAD), but the extent of this contribution is unknown. Our objective was to estimate the contribution of Lp(a) to polygenic risk of CAD and to evaluate the respective contributions of Lp(a) and a CAD polygenic risk score (PRS) to CAD. A total of 372 385 UK Biobank participants of European ancestry free of CAD at baseline were included. Plasma Lp(a) levels were measured and a CAD-PRS was calculated using the LDpred2 algorithm. Over the median follow-up of 12.6 years, 13 538 participants had incident CAD (myocardial infarction, coronary artery bypass grafting, or coronary angioplasty). The LPA region contribution to the CAD-PRS-mediated CAD risk was modest (7.2% [95% CI, 6.1-8.3]). Lp(a) levels significantly increased the predictive performance of a CAD-PRS including age and sex in Cox regression (C statistic 0.751 versus 0.746, difference, 0.005 [95% CI, 0.004-0.006]). Compared with participants in the bottom CAD-PRS quintile with Lp(a) levels <25 nmol/L (CAD event rate, 1.4%), the hazard ratio for incident CAD in participants in the top CAD-PRS quintile with Lp(a) levels ≥125 nmol/L was 5.45 (95% CI, 4.93-6.03; P=9.35×10-242, CAD event rate 6.6%). Compared with individuals with a low genetic risk of CAD (low CAD-PRS and low Lp[a] levels), those with a high genetic risk (high CAD-PRS and high Lp[a] levels) had a 5-fold higher CAD risk. These results highlight a substantial contribution of genetic risk factors to CAD and that accurate estimation of genetic risk of CAD may need to consider blood levels of Lp(a).

Impact of Lipoprotein (a) on Long-Term Outcomes in Patients With Acute Myocardial Infarction.

Lipoprotein (a) (Lp(a)) is a complex circulating lipoprotein, and there is increasing evidence it is a risk factor for atherosclerotic cardiovascular disease (ASCVD). This study aimed to investigate the influence of Lp(a) serum levels on long-term outcomes after acute myocardial infarction (AMI). Between January 2015 and January 2018, we enrolled 262 patients with AMI who underwent coronary angiography within 24 h of the onset of chest pain and had available Lp(a) data enabling subdivision into 2 groups: high Lp(a) (≥32 mg/dL: n=76) and low Lp(a) (<32 mg/dL: n=186). The primary endpoint was major adverse cardiac events (MACE), which was defined as a composite of cardiac death, nonfatal MI, and readmission for heart failure. Multivariate Cox regression analysis was performed to identify the predictors of MACE. The incidence of MACE was significantly higher in the high Lp(a) group than in the low Lp(a) group (32.8% vs. 19.6%, P=0.004). Multivariate analysis showed that Lp(a) ≥32 mg/dL was an independent predictor of MACE (hazard ratio 2.84, 95% confidence interval 1.25-6.60, P=0.013). High Lp(a) levels were associated with worse long-term outcomes after AMI, so Lp(a) may be useful for risk assessment.