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Lipoprotein(a) [Lp(a)] contributes to cardiovascular disease risk. A genetically determined size polymorphism in apolipoprotein(a) [apo(a)], determined by the number of Kringle (K) repeats, inversely regulates Lp(a) levels. Nongenetic factors including dietary saturated fat influence Lp(a) levels. However, less is known about the effects of carbohydrates including dietary sugars. In this double-blind, parallel arm study among 32 overweight/obese adults, we investigated the effect of consuming glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks on Lp(a) level and assessed the role of the apo(a) size polymorphism. The mean (±SD) age of participants was 54 ± 8 years, 50% were women, and 75% were of European descent. Following the 10-week intervention, Lp(a) level was reduced by an average (±SEM) of -13.2% ± 4.3% in all participants (P = 0.005); -15.3% ± 7.8% in the 15 participants who consumed glucose (P = 0.07); and -11.3% ± 4.5% in the 17 participants who consumed fructose (P = 0.02), without any significant difference in the effect between the two sugar groups. Relative changes in Lp(a) levels were similar across subgroups of lower versus higher baseline Lp(a) level or carrier versus noncarrier of an atherogenic small (≤22K) apo(a) size. In contrast, LDL-C increased. In conclusion, in older, overweight/obese adults, consuming sugar-sweetened beverages reduced Lp(a) levels by ∼13% independently of apo(a) size variability and the type of sugar consumed. The Lp(a) response was opposite to that of LDL-C and triglyceride concentrations. These findings suggest that metabolic pathways might impact Lp(a) levels.

BACKGROUND: Higher lipoprotein(a) and oxidized phospholipid concentrations are associated with increased risk for coronary artery disease and valvular heart disease. The role of lipoprotein(a) or oxidized phospholipid as a risk factor for incident heart failure (HF) or its complications remains uncertain. METHODS AND RESULTS: A total of 1251 individuals referred for coronary angiography in the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study were stratified on the basis of universal definition of HF stage; those in stage A/B (N=714) were followed up for an average 3.7 years for incident stage C/D HF or the composite of HF/cardiovascular death. During follow-up, 105 (14.7%) study participants in stage A/B progressed to symptomatic HF and 57 (8.0%) had cardiovascular death. In models adjusted for multiple HF risk factors, including severe coronary artery disease and aortic stenosis, individuals with lipoprotein(a) ≥150 nmol/L were at higher risk for progression to symptomatic HF (hazard ratio [HR], 1.90 [95% CI, 1.15-3.13]; P=0.01) or the composite of HF/cardiovascular death (HR, 1.71 [95% CI, 1.10-2.67]; P=0.02). These results remained significant after further adjustment of the model to include prior myocardial infarction (HF: HR, 1.89, P=0.01; HF/cardiovascular death: HR, 1.68, P=0.02). Elevated oxidized phospholipid concentrations were similarly associated with risk, particularly when added to higher lipoprotein(a). In Kaplan-Meier analyses, individuals with stage A/B HF and elevated lipoprotein(a) had shorter time to progression to stage C/D HF or HF/cardiovascular death (both log-rank P

OBJECTIVE: Lipoprotein(a) [Lp(a)] is an atherogenic and prothrombotic lipoprotein associated with atherosclerotic cardiovascular disease (ASCVD). We assessed the association between regular aspirin use and ASCVD mortality among individuals with versus without elevated Lp(a) in a nationally representative US cohort. METHODS: Eligible participants were aged 40-70 years without clinical ASCVD, reported on aspirin use, and had Lp(a) measurements from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994), the only cycle of this nationally representative US cohort to measure Lp(a). Regular aspirin use was defined as taking aspirin ≥30 times in the previous month. Using NHANES III linked mortality records and weighted Cox proportional hazards regression, the association between regular aspirin use and ASCVD mortality was observed in those with and without elevated Lp(a) (≥50 versus

PURPOSE OF REVIEW: Cardiovascular disease is a leading cause of death worldwide. Dyslipidemia is a critical modifiable risk factor for the prevention of cardiovascular disease. Dyslipidemia affects a large population of women and is especially pervasive within racial/ethnic minorities. RECENT FINDINGS: Dyslipidemia in pregnancy leads to worse outcomes for patients and creates increased cardiovascular risk for women at an older age. However, women remain underscreened and undertreated compared to men. Females also comprise a small portion of clinical trial participants for lipid lowering agents with increased disease prevalence compared to trial representation. However, recent lipid trials have shown different efficacies of therapies such as ezetimibe, inclisiran, and bempedoic acid with a greater relative benefit for women. SUMMARY: Pathophysiology of dyslipidemia varies between men and women and across a womans lifetime. While increased lipid levels or lipid imbalances are more common in postmenopausal women over age 50, conditions such as PCOS and FH produce higher cardiovascular risk for young women.Best practices for management of women with dyslipidemia include early screening with lifestyle intervention and pharmacotherapy with statin and non-statin agents to achieve guideline directed LDL-C thresholds.

BACKGROUND: 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). METHODS: 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. RESULTS: 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]). CONCLUSIONS: 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.

BackgroundEffective therapies for reducing cardiovascular disease (CVD) risk in people with elevated lipoprotein(a) are lacking, especially for primary prevention. Because of the potential association of lipoprotein(a) with thrombosis, we evaluated the relationship between aspirin use and CVD events in people with elevated lipoprotein(a).Methods and resultsWe used data from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of baseline cardiovascular disease. Due to potential confounding by indication, we matched aspirin users to nonusers using a propensity score based on CVD risk factors. We then evaluated the association between aspirin use and coronary heart disease (CHD) events (CHD death, nonfatal myocardial infarction) stratified by baseline lipoprotein(a) level (threshold of 50 mg/dL) using Cox proportional hazards models with adjustment for CVD risk factors. After propensity matching, the study cohort included 2183 participants, including 1234 (57%) with baseline aspirin use and 423 (19%) with lipoprotein(a) >50 mg/dL. Participants with lipoprotein(a) >50 mg/dL had a higher burden of CVD risk factors, more frequent aspirin use (61.7% versus 55.3%, P=0.02), and higher rate of incident CHD events (13.7% versus 8.9%, P50 mg/dL and aspirin use had similar CHD risk as those with lipoprotein(a) ≤50 mg/dL regardless of aspirin use.ConclusionsAspirin use was associated with a significantly lower risk for CHD events in participants with lipoprotein(a) >50 mg/dL without baseline CVD. The results of this observational propensity-matched study require confirmation in studies with randomization of aspirin use.

BACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE). METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. RESULTS: Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. CONCLUSIONS: In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Oxidized phospholipids (OxPLs) are carried by apolipoprotein B-100–containing lipoproteins (OxPL-apoB) including lipoprotein(a) (Lp[a]). Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD). This study aimed to evaluate the associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD. OxPL-apoB and Lp(a) were evaluated in MESA (Multi-Ethnic Study of Atherosclerosis) and a participant-level meta-analysis of 4 randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity) was evaluated using multivariable linear regression models. In MESA, both OxPL-apoB and Lp(a) were associated with prevalent AVC (OR per SD: 1.19 [95% CI: 1.07-1.32] and 1.13 [95% CI: 1.01-1.27], respectively) with a significant interaction between the two (P < 0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated individually (interaction P < 0.01). The OxPL-apoB∗Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were associated with faster increase in peak aortic valve jet velocity, but when evaluated together, only OxPL-apoB remained significant (ß: 0.07; 95% CI: 0.01-0.12). OxPL-apoB is a predictor of the presence, incidence, and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels, and may represent a novel therapeutic target for CAVD. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Dyslipidaemia, inflammation and elevated Lp(a) levels are associated with the progression of atherosclerosis. This study investigates whether patients with a first‐time presentation of chest pain and on‐target LDL‐C levels and intermediate FRS/ESC‐Score risks, display a high inflammatory burden linked to myocardial injury and whether inflammation at admission affects the re‐event rate up to 6 years follow‐up. Methods: Blind assessments of novel inflammatory markers such as Glycoprotein A and B via nuclear magnetic resonance (NMR), cytokines, hsCRP, Neutrophil‐to‐Lymphocyte ratio (NLR) and Lipoprotein(a) levels were examined. Out of 198 chest pain patients screened, 97 met the inclusion criteria at admission. Results: cTnI(+) patients (>61 ng/L) with elevated Lipoprotein(a), showed significantly increased levels of Glycoprotein A and B, hsCRP, IL‐6, a high NLR and a reduced left ventricular ejection fraction (%) compared to cTnI(−) individuals. Those patients, with a higher inflammatory burden at hospital admission (hsCRP, IL‐6, Glycoprotein A and B, and Lipoprotein(a)) had a higher re‐event rate at follow‐up. Conclusions: Inflammation and Lipoprotein(a) levels were particularly prominent in patients presenting with reduced left ventricular ejection fraction. Notably, Glycoproteins A/B emerge as novel markers of inflammation in these patients. Our study highlights the significantly higher impact of inflammatory burden in patients with chest pain and high level of myocardial damage than in those with lower myocardial affectation, even when they all had lipid levels well controlled. Inflammation at the time of admission influenced the re‐event rate over a follow‐up period of up to 6 years. [ABSTRACT FROM AUTHOR]

Background: Lipoprotein(a) (Lp(a)) is a causal, genetically determined risk factor for cardiovascular disease (CVD) in the general population. Patients with chronic kidney disease (CKD) have an increased CVD risk and elevated Lp(a) concentrations. Only a few studies on Lp(a) were performed in persons with mild‐to‐moderate CKD; none of them used genetic variants to explore potential causal associations. Objectives: This study aims to investigate the association of measured and genetically predicted Lp(a) concentrations on prevalent and incident CVD events in the German Chronic Kidney Disease (GCKD) study. Methods: The study included 5043 participants of European ancestry with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2 or an eGFR >60 mL/min/1.73 m2 in the presence of overt albuminuria with a follow‐up of 6.5 years. Results: With each 10 mg/dL higher Lp(a) concentration, odds for prevalent CVD (1290 events) increased 1.065‐fold (95%CI: 1.042–1.088, p < 0.001). The risk was significantly higher in patients with Lp(a) ≥50 mg/dL but most pronounced in Lp(a) ≥70 mg/dL (odds ratio = 1.775 [1.409–2.231], p < 0.001) compared to Lp(a) <30 mg/dL. Each 10 mg/dL higher Lp(a) concentration and Lp(a) ≥70 mg/dL increased the risk for incident 3‐point major adverse cardiovascular events (MACEs) (474 events): hazard ratio [HR] = 1.037 [1.009–1.067], p = 0.009 and HR = 1.335 [1.001–1.781], p = 0.050), respectively. Similar results were obtained for 4‐point MACE (653 events). Analyses based on apo(a) isoforms and genetically predicted Lp(a) concentrations led to even stronger associations. Conclusions: In patients with mild‐to‐severe CKD, elevated Lp(a) concentrations and genetic determinants of Lp(a) concentrations are significantly associated with CVD at baseline and during follow‐up, independent of traditional risk factors. [ABSTRACT FROM AUTHOR]

Background and purpose: Elevated serum lipoprotein(a) (Lp[a]) levels have been linked to an increased incidence of stroke. This systematic review and meta‐analysis aimed to evaluate the impact of serum Lp(a) on the functional outcomes of patients with ischemic stroke (IS). Methods: We conducted a comprehensive search of the MEDLINE, Web of Science, Embase, Wanfang, and China National Knowledge Infrastructure databases to identify relevant cohort studies. A random effects model was utilized to synthesize the data, accounting for study heterogeneity. Results: The analysis included 11 cohort studies comprising 11,958 patients with IS. Pooled results indicated that high baseline Lp(a) levels were associated with an increased risk of poor functional outcomes during follow‐up (odds ratio [OR] = 2.13, 95% confidence interval = 1.67–2.71, p < 0.001, I2 = 62%). Subgroup analyses revealed that the relationship between high Lp(a) levels and the risk of poor functional outcomes was more pronounced at discharge (OR = 3.25), 3 months (OR = 2.02), and 6 months (OR = 2.11) poststroke, compared to 12 months (OR = 1.25, p for subgroup difference < 0.001). Furthermore, the association was attenuated yet remained significant in studies adjusting for low‐density lipoprotein cholesterol (LDL‐C) compared to those that did not adjust for LDL‐C (OR = 1.69 vs. 2.63, p for subgroup difference = 0.03). Conclusions: High serum Lp(a) levels at baseline are significantly associated with poor functional outcomes in patients with IS. [ABSTRACT FROM AUTHOR]

Purpose: This meta-analysis aimed to clarify the correlation between serum lipoprotein(a) [Lp(a)] levels and diabetic retinopathy (DR) in type 2 diabetes (T2D) individuals. Methods: We searched electronic databases, including PubMed, Web of Science, and Embase, for relevant observational studies evaluating the association between serum Lp(a) levels and the risk of DR. Odds ratios (ORs) with 95% confidence intervals (CIs) were summarized to indicate the association between a high Lp(a) and the risk of DR. Data were extracted and pooled using a random-effects model to account for variability among studies. Heterogeneity was assessed using the I2 statistic, and publication bias was evaluated through funnel plots and Egger's test. Results: Eleven observational studies were included. Compared to T2D patients of the lowest Lp(a) category, those of the highest Lp(a) category were associated with a higher risk of DR (OR: 2.05, 95% CI: 1.43–2.93, I2 = 83%, p < 0.001). Subgroup analyses suggested this association was predominantly observed in cross-sectional and case–control studies but not cohort studies (p for subgroup differences = 0.03). Additionally, the link between Lp(a) and DR was consistent across variables such as study country, Lp(a) cutoff values, analysis model (univariate or multivariate), and adjustment for concurrent medication use. A further meta-analysis suggested a significant relationship between elevated Lp(a) levels and proliferative DR (OR: 1.90, 95% CI: 1.03–3.48, I2 = 86%, p = 0.04). Conclusion: Elevated serum Lp(a) levels are associated with an increased risk of DR in individuals with T2D. [ABSTRACT FROM AUTHOR]

Background: Lipoprotein(a) [Lp(a)] is recognized as an independent risk factor for cardiovascular diseases; however, the impact of fat-based diets on its levels remains unclear. Objective: This study aims to assess and analyze current evidence on the impact of various types of fat-based diets on Lp(a) levels. Material and Methods: A comprehensive search of the PubMed database was conducted on 9 July 2024, focusing on clinical and randomized trials published since 2000. Out of 697 identified studies, 33 met the inclusion criteria and were selected for analysis. Results: The findings suggest that modifications in fat-based diets, particularly concerning the type and amount of consumed fats and fatty acids, can significantly influence plasma Lp(a) levels. Diets rich in unsaturated fats, including polyunsaturated and monounsaturated fatty acids, were associated with more favorable effects in lowering Lp(a) levels. In contrast, diets high in saturated fats were linked to elevated Lp(a) levels. However, these conclusions were not consistent across all studies considered. Conclusions: This work highlights the importance of a personalized dietary approach, considering both genetic predispositions and dietary habits. While diet alone may not drastically alter Lp(a) levels due to their strong genetic determination, a comprehensive strategy involving a healthy diet rich in unsaturated fats, regular physical activity, and effective weight management is recommended to reduce the risk of cardiovascular diseases. Further research is needed to clarify the mechanisms through which different fats affect Lp(a) and to develop targeted dietary recommendations. [ABSTRACT FROM AUTHOR]

Recent studies have shown that lipoprotein(a) (Lp(a)) is an important risk factor for a plethora of different cardiovascular diseases. It has been proven that Lp(a) levels are genetically determined and correlate with risk of cardiovascular disease, independent of lifestyle factors. As of yet, treatment options to reduce Lp(a) levels are limited, but new research into Lp(a) reduction yields promising results. This review delves into Lp(a)'s biochemistry and mechanism of effect, the association between Lp(a) and cardiovascular diseases, and possible therapies to minimise cardiovascular disease. [ABSTRACT FROM AUTHOR]

Calcified areas in aortic valves often co-localize with amyloid fibrils that can promote calcification. Patient-derived amyloid fibrils contain arrays of acidic residues that can bind calcium and organize calcium phosphate nucleation clusters, while collagen fibrils guide crystal growth. This process is akin to functional biomineralization guided by Ca entrapment by acidic arrays in proteins, including amyloids. High shear stress and turbulent blood flow across the aortic valve, which are exacerbated in calcific aortic valve disease (CAVD), augment amyloid formation by plasma proteins. The main amyloid protein is probably apolipoprotein A-I (apoA-I), yet other proteins can also be involved. Lipoprotein(a) [Lp(a)], a genetic risk factor for CAVD, contributes to calcification. Enzymatic hydrolysis of oxidized phospholipids in Lp(a) helps generate orthophosphate, whereas apo(a) blocks collagen and amyloid fibril degradation by plasmin. Calcific aortic valve disease (CAVD) is a widely prevalent heart disorder in need of pharmacological interventions. Calcified areas in aortic valves often contain amyloid fibrils that promote calcification in vitro. This opinion paper suggests that amyloid contributes to CAVD development; amyloid-assisted nucleation can accelerate hydroxyapatite deposition onto collagen matrix. Notably, acidic arrays in amyloid match calcium–calcium spacing in the amorphous hydroxyapatite precursor, while oscillating hemodynamic perturbations promote amyloid deposition in the valve. Lipoprotein(a), a genetic risk factor for CAVD, augments calcification via several mechanisms, wherein hydrolysis of oxidized phospholipids (oxPLs) by Lp(a)-associated enzymes helps generate orthophosphate, and apolipoprotein(a) blocks plasmin-induced fibril degradation. Current studies of amyloid–calcium–collagen interactions in solution and in fibrillar complexes allow deeper insight into the role of amyloid in calcification. [ABSTRACT FROM AUTHOR]

Lipoprotein(a) [Lp(a)] is an emerging predictor for atherosclerotic cardiovascular disease (ASCVD) but the association from a perspective on current risk stratification was unknown. A cohort of 9944 Chinese patients with ASCVD was recruited and refined into very‐high‐risk (VHR) and non‐VHR subgroups according to current guideline. Lp(a) plasma levels were divided by its concentration (<30, 30–50, 50–75, and ≥75 mg/dL) and percentile zones (<25th, 25–50th, 50–75th, 75–90th, ≥90th). Cardiovascular events (CVEs) occurred during an average of 38.5 months' follow‐up were recorded. We found that Lp(a) was increased with risk stratification of ASCVD increasing. Prevalence of CVEs had a significantly increasing trend with gradients of Lp(a) elevation in VHR but not in non‐VHR subgroup. The adjusted HRs (95%CIs) for CVEs were 1.75(1.25–2.46) in the highest group of Lp(a) ≥75 mg/dL compared with the group of Lp(a) <30 mg/dL as the reference in overall patients, 2.18(1.32–3.58) in VHR subgroup and 1.43(0.93–2.18) in non‐VHR subgroup, respectively. The adjusted HRs (95%CIs) at the highest grade of Lp(a) levels (≥90th) were 1.72(1.19–2.50) in overall population, 2.83(1.53–5.24) in VHR subgroup and 1.38(0.86–2.12) in non‐VHR subgroup, respectively. These findings suggested that Lp(a) might contribute more to CVEs risk in VHR subgroup of ASCVD. [ABSTRACT FROM AUTHOR]

Quantitative protein mass spectrometry (MS) is ideally suited for precision diagnostics and for reference standardization of protein analytes. At the Leiden Apolipoprotein Reference Laboratory we apply MS strategies to obtain detailed insight into the protein-to-peptide conversion in order to verify that quantifier peptides are not partly concealed in miscleaved protein backbone.Apolipoprotein(a) (apo(a)) was digested in a non-optimal manner to enhance the number of miscleaved peptides that were identified by high resolution liquid chromatography tandem-MS measurements. The protein-to-peptide conversion was carefully mapped with specific attention for miscleaved peptides that contain an apo(a) quantifier peptide. Four different isotopologues of each apo(a)-quantifier peptide were applied to evaluate linearity of internal peptide standards during measurement of specific real-life samples.Two apo(a) quantifier peptides that were concealed in two different miscleaved peptides were included into a multiple reaction monitoring list in our targeted MS-based apo(a) quantifications to alert for potential protein digestion discrepancies. The presence of miscleaved peptides could be ruled out when applying our candidate reference measurement procedure (RMP) for apo(a) quantification.These data further corroborate the validity of our apo(a) candidate RMP as higher order method for certification of commercial Lp(a) tests that is endorsed by the International Federation of Clinical Chemistry and Laboratory Medicine. MS-based molecular detection and quantification of heterogeneous apo(a) proteoforms will allow manufacturers’ transitioning from confounded lipoprotein(a) [Lp(a)] mass levels into accurate molar apo(a) levels. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions Although nonalcoholic fatty liver disease (NAFLD) and lipoprotein(a) [Lp(a)] are associated with cardiovascular diseases, existing data on Lp(a) in NAFLD are conflicting. The aim of this systematic review and meta‐analysis was to summarize and compare data on circulating Lp(a) between NAFLD patients and non‐NAFLD controls.A systematic literature search was performed in PubMed, Scopus, and Cochrane Library. This meta‐analysis included 18 studies containing data on 74 691 individuals (20 220 patients with NAFLD and 54 471 controls).Circulating Lp(a) was similar between patients with NAFLD and controls (standardized mean difference [SMD] 0.09; 95% confidence interval [95% CI] −0.21, 0.38). The heterogeneity among studies was high (I2 = 100%); no publication bias was detected (Egger's test P = 0.941). However, in subgroup analysis, Lp(a) was lower in NAFLD patients than controls, when Lp(a) was measured with nephelometry (SMD ‐0.26; 95% CI ‐0.46, −0.06), but not turbidimetry; this analysis also resulted in mild reduction of heterogeneity within the subgroup of nephelometry (I2 = 87%). The sensitivity analyses, based on the exclusion of studies with Newcastle‐Ottawa Scale score ≤6 (n = 5), studies in which liver biopsy was used for NAFLD diagnosis (n = 4) or studies that adopted the criteria of metabolic dysfunction‐associated fatty liver disease (n = 2), and meta‐regression analysis did not explain the high heterogeneity among studies.Overall, circulating Lp(a) was similar between NAFLD patients and non‐NAFLD controls; however, patients with NAFLD had lower circulating Lp(a) compared with controls, when Lp(a) was measured with nephelometry. These results should be cautiously interpreted, because of the high heterogeneity among studies. [ABSTRACT FROM AUTHOR]

Lipoprotein (a) is a complex lipid molecule that has sparked immense interest in recent years, after studies demonstrated its significant association with several cardiovascular conditions. Lp(a) promotes cardiovascular disease through its combined proatherogenic, pro-inflammatory, and prothrombotic effects. While the measurement of Lp(a) has become widely available, effective methods to reduce its concentration are currently limited. However, emerging data from ongoing clinical trials involving antisense oligonucleotides have indicated promising outcomes in effectively reducing Lp(a) concentrations. This may serve as a potential therapeutic target in the management and prevention of myocardial infarction, calcific aortic stenosis, and cerebrovascular accidents. In contrast, the role of Lp(a) in atrial fibrillation, in-stent restenosis, cardiac allograft vasculopathy, and bioprosthetic aortic valve degeneration remains unclear. This review article aims to thoroughly review the existing literature and provide an updated overview of the evidence surrounding the association of Lp(a) and these cardiovascular diseases. We seek to highlight controversies in the existing literature and offer directions for future investigations to better understand Lp(a)'s precise role in these conditions, while providing a summary of its unique molecular characteristics. [ABSTRACT FROM AUTHOR]

Background: Repetitive genome regions, such as variable number of tandem repeats (VNTR) or short tandem repeats (STR), are major constituents of the uncharted dark genome and evade conventional sequencing approaches. The protein-coding LPA kringle IV type-2 (KIV-2) VNTR (5.6 kb per unit, 1–40 units per allele) is a medically highly relevant example with a particularly intricate structure, multiple haplotypes, intragenic homologies, and an intra-VNTR STR. It is the primary regulator of plasma lipoprotein(a) [Lp(a)] concentrations, an important cardiovascular risk factor. Lp(a) concentrations vary widely between individuals and ancestries. Multiple variants and functional haplotypes in the LPA gene and especially in the KIV-2 VNTR strongly contribute to this variance. Methods: We evaluated the performance of amplicon-based nanopore sequencing with unique molecular identifiers (UMI-ONT-Seq) for SNP detection, haplotype mapping, VNTR unit consensus sequence generation, and copy number estimation via coverage-corrected haplotypes quantification in the KIV-2 VNTR. We used 15 human samples and low-level mixtures (0.5 to 5%) of KIV-2 plasmids as a validation set. We then applied UMI-ONT-Seq to extract KIV-2 VNTR haplotypes in 48 multi-ancestry 1000 Genome samples and analyzed at scale a poorly characterized STR within the KIV-2 VNTR. Results: UMI-ONT-Seq detected KIV-2 SNPs down to 1% variant level with high sensitivity, specificity, and precision (0.977 ± 0.018; 1.000 ± 0.0005; 0.993 ± 0.02) and accurately retrieved the full-length haplotype of each VNTR unit. Human variant levels were highly correlated with next-generation sequencing (R2 = 0.983) without bias across the whole variant level range. Six reads per UMI produced sequences of each KIV-2 unit with Q40 quality. The KIV-2 repeat number determined by coverage-corrected unique haplotype counting was in close agreement with droplet digital PCR (ddPCR), with 70% of the samples falling even within the narrow confidence interval of ddPCR. We then analyzed 62,679 intra-KIV-2 STR sequences and explored KIV-2 SNP haplotype patterns across five ancestries. Conclusions: UMI-ONT-Seq accurately retrieves the SNP haplotype and precisely quantifies the VNTR copy number of each repeat unit of the complex KIV-2 VNTR region across multiple ancestries. This study utilizes the KIV-2 VNTR, presenting a novel and potent tool for comprehensive characterization of medically relevant complex genome regions at scale. [ABSTRACT FROM AUTHOR]

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The fact that lipoprotein(a) levels should be regarded as a causal residual risk factor in the atherosclerotic cardiovascular diseases (ASCVD) is now a no-brainer. This review article aims to summarize the latest evidence supporting the causal role of lipoprotein(a) in ASCVD and the potential strategies to reduce the lipoprotein(a) burden until clinical trial results are available. Epidemiological and genetic data demonstrate the causal link between lipoprotein(a) and increased ASCVD risk. That being said, a specific question comes to mind: “must we wait for outcome trials in order to take action?”. Given that lipoprotein(a) levels predict incident ASCVD in both primary and secondary prevention contexts, with a linear risk gradient across its distribution, measuring lipoprotein(a) can unequivocally help identify patients who may later benefit from specific lipoprotein(a)-lowering therapies. This understanding has led various National Societies to recommend dosing lipoprotein(a) in high-risk individuals and to support the recommendation of measuring lipoprotein(a) levels at least once in every adult for risk stratification.

Hui-Hui Yang,1,&ast; Jie Dou,1,&ast; Ruo-Ling Guo,1 Jie Gao,1 Hui-Zhe Li,2 Kun Wang,2 Tian-Hua Hou,2 Tie-Jun Wei,2 Jing-Tao Guo,2 Jian-Wei Liu,3 Dong-Lei Luo2 1Chengde Medical University, Chengde, People’s Republic of China; 2Department of Cardiology, Chengde Central Hospital/Second Clinical College of Chengde Medical University, Chengde, People’s Republic of China; 3Department of Cardiothoracic Interventional Vascular Surgery, Chengde Central Hospital/Second Clinical College of Chengde Medical University, Chengde, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong-Lei Luo, Department of Cardiology, Chengde Central Hospital/Second Clinical College of Chengde Medical, Chengde, People’s Republic of China, Email dongleiluocn@aliyun.com Jian-Wei Liu, Department of Cardiothoracic Interventional Vascular Surgery, Chengde Central Hospital/Second Clinical College of Chengde Medical University, Chengde, People’s Republic of China, Email Ljw2112@126.comObjective: The study aimed to explore the clinical diagnostic significance of lipoprotein(a) [Lp(a)] and neck circumference (NC) in patients with coronary heart disease (CHD).Methods: This cross-sectional study was conducted at Chengde Central Hospital from September 2021 to June 2023, enrolling 791 patients with suspected CHD who underwent selective coronary angiography (CAG). Patients were categorized into CHD and non-CHD groups based on the severity of arterial narrowing. Subsequently, the diagnostic value of Lp(a) combined with NC in patients with CHD was assessed using receiver operating characteristic (ROC) curves. Based on the results of multivariate logistic regression, a nomogram was constructed, and its clinical applicability was validated using decision curve analysis (DCA) and clinical impact curve (CIC).Results: Multivariate logistic regression proved that high Lp(a) and high NC are risk factors for CHD, with OR of 1.836 (95% CI: 1.282– 2.630) and 1.383 (1.0.978– 1.955), respectively. Patients in the high NC or Lp(a) group exhibited a higher prevalence of multi-vessel disease. The area under the ROC curve (AUC) of the predictive model combining high Lp(a) and high NC was 0.710 (95% CI: 0.670– 0.751) and also demonstrated good calibration (Hosmer-Lemeshow goodness-of-fit test P value=0.494). The DCA and CIC confirmed the clinical utility of the nomogram developed to predict CHD based on the combination of high Lp(a) and high NC.Conclusion: The levels of Lp(a) and NC exhibit a significant correlation with the presence of CHD, and their combined assessment holds specific clinical value in the diagnosis of CHD.Keywords: coronary heart disease, lipoprotein(a), neck circumference, sensitivity, specificity

Abstract Background Repetitive genome regions, such as variable number of tandem repeats (VNTR) or short tandem repeats (STR), are major constituents of the uncharted dark genome and evade conventional sequencing approaches. The protein-coding LPA kringle IV type-2 (KIV-2) VNTR (5.6 kb per unit, 1–40 units per allele) is a medically highly relevant example with a particularly intricate structure, multiple haplotypes, intragenic homologies, and an intra-VNTR STR. It is the primary regulator of plasma lipoprotein(a) [Lp(a)] concentrations, an important cardiovascular risk factor. Lp(a) concentrations vary widely between individuals and ancestries. Multiple variants and functional haplotypes in the LPA gene and especially in the KIV-2 VNTR strongly contribute to this variance. Methods We evaluated the performance of amplicon-based nanopore sequencing with unique molecular identifiers (UMI-ONT-Seq) for SNP detection, haplotype mapping, VNTR unit consensus sequence generation, and copy number estimation via coverage-corrected haplotypes quantification in the KIV-2 VNTR. We used 15 human samples and low-level mixtures (0.5 to 5%) of KIV-2 plasmids as a validation set. We then applied UMI-ONT-Seq to extract KIV-2 VNTR haplotypes in 48 multi-ancestry 1000 Genome samples and analyzed at scale a poorly characterized STR within the KIV-2 VNTR. Results UMI-ONT-Seq detected KIV-2 SNPs down to 1% variant level with high sensitivity, specificity, and precision (0.977 ± 0.018; 1.000 ± 0.0005; 0.993 ± 0.02) and accurately retrieved the full-length haplotype of each VNTR unit. Human variant levels were highly correlated with next-generation sequencing (R 2 = 0.983) without bias across the whole variant level range. Six reads per UMI produced sequences of each KIV-2 unit with Q40 quality. The KIV-2 repeat number determined by coverage-corrected unique haplotype counting was in close agreement with droplet digital PCR (ddPCR), with 70% of the samples falling even within the narrow confidence interval of ddPCR. We then analyzed 62,679 intra-KIV-2 STR sequences and explored KIV-2 SNP haplotype patterns across five ancestries. Conclusions UMI-ONT-Seq accurately retrieves the SNP haplotype and precisely quantifies the VNTR copy number of each repeat unit of the complex KIV-2 VNTR region across multiple ancestries. This study utilizes the KIV-2 VNTR, presenting a novel and potent tool for comprehensive characterization of medically relevant complex genome regions at scale.

AimsStudies have indicated inconsistent results regarding the association between plasma levels of Lipoprotein(a) [Lp(a)] and coronary artery calcification (CAC). We performed a systematic review and meta-analysis to investigate the association between elevated levels of Lp(a) and risk of CAC in populations free of cardiovascular disease (CVD) symptoms.Data synthesisPubMed, Web of Science, Embase, and Scopus were searched up to July 2022 and the methodological quality was assessed using Newcastle-Ottawa Scale (NOS) scale. Random-effects meta-analysis was used to estimate pooled odds ratio (OR) and 95% confidence interval. Out of 298 studies, data from 8 cross-sectional (n = 18,668) and 4 cohort (n = 15,355) studies were used in meta-analysis. Cohort studies demonstrated a positive significant association between Lp(a) and CAC, so that individuals with Lp(a)≥30-50 exposed to about 60% risk of CAC incidence compared to those with lower Lp(a) concentrations in asymptomatic CVD subjects (OR, 1.58; 95% CI, 1.38-1.80; l2, 0.0%; P, 0.483); Subgroup analysis showed that a cut-off level for Lp(a) measurement could not statistically affect the association, but race significantly affected the relationship between Lp(a) and CAC (OR,1.60; 95% CI, 1.41-1.81). Analyses also revealed that both men and women with higher Lp(a) concentrations are at the same risk for increased CAC.ConclusionsBlood Lp(a) level was significantly associated with CAC incidence in asymptomatic populations with CVD, indicating that measuring Lp(a) may be a useful biomarker for diagnosing subclinical atherosclerosis in individuals at higher risk of CAC score.Prospero registration numberCRD42022350297.

PURPOSE OF REVIEW: Lipoprotein(a) [Lp(a)] is causally associated with cardiovascular diseases, and elevated levels are highly prevalent. However, there is a lack of available therapies to address Lp(a)-mediated risk. Though aspirin has progressively fallen out of favor for primary prevention, individuals with high Lp(a) may represent a high-risk group that derives a net benefit. RECENT FINDINGS: Aspirin has been demonstrated to have a clear benefit in secondary prevention of cardiovascular disease, but recent primary prevention trials have at best demonstrated a small benefit. However, individuals with elevated Lp(a) may be of high risk enough to benefit, particularly given interactions between Lp(a) and the fibrinolytic system / platelets, and the lack of available targeted medical therapies. In secondary analyses of the Womens Health Study (WHS) and the Aspirin in Reducing Events in the Elderly (ASPREE) trial, aspirin use was associated with a significant reduction in cardiovascular events in carriers of genetic polymorphisms associated with elevated Lp(a) levels. Further studies are needed, however, as these studies focused on narrower subsets of the overall population and genetic markers. SUMMARY: Individuals with elevated Lp(a) may benefit from aspirin therapy in primary prevention, but further study with plasma Lp(a) levels, broader populations, and randomization of aspirin are needed.

Purpose of reviewLipoprotein(a) is an independent risk factor for cardiovascular disease. We review the ongoing shifts in consensus guidelines for the testing and management of Lp(a) and provide insight into whether current evidence suggests that awareness and testing of Lp(a) is clinically actionable.Recent findingsGWAS and Mendelian randomization studies have established causal links between elevated Lp(a) and forms of CVD, including CAD and calcific aortic valve disease. Testing of Lp(a) identifies patients with similar risk to that of heterozygous FH, enhances risk stratification in patients with borderline/intermediate risk as determined through traditional factors, and facilitates the assessment of inherited CVD risk through cascade screening in patients with known family history of elevated Lp(a). Reductions in Lp(a) through non-targeted therapies including PCSK9 inhibition and lipoprotein apheresis have demonstrated reductions in ASCVD risk that are likely attributable to lowering Lp(a). Targeted therapies to potently lower Lp(a) are in clinical development. Lp(a) is actionable, and can be used to identify high risk patients for primary prevention and their family members through cascade screening, and to guide intensification of therapy in primary and secondary prevention of ASCVD.

Abstract Background Retention of apolipoprotein B (apoB)-containing lipoproteins within the arterial wall plays a major causal role in atherosclerotic cardiovascular disease (ASCVD). There is a single apoB molecule in all apoB-containing lipoproteins. Therefore, quantitation of apoB directly estimates the number of atherogenic particles in plasma. ApoB is the preferred measurement to refine the estimate of ASCVD risk. Low-density lipoprotein (LDL) particles are by far the most abundant apoB-containing particles. In patients with elevated lipoprotein(a) (Lp(a)), apoB may considerably underestimate risk because Mendelian randomization studies have shown that the atherogenicity of Lp(a) is approximately 7-fold greater than that of LDL on a per apoB particle basis. In subjects with increased Lp(a), the association between LDL-cholesterol and incident CHD (coronary heart disease) is increased, but the association between apoB and incident CHD is diminished or even lost. Thus, there is a need to understand the mechanisms of Lp(a), LDL-cholesterol and apoB-related CHD risk and to provide clinicians with a simple practical tool to address these complex and variable relationships. How can we understand a patient’s overall lipid-driven atherogenic risk? What proportion of this risk does apoB capture? What proportion of this risk do Lp(a) particles carry? To answer these questions, we created a novel metric of atherogenic risk: risk-weighted apolipoprotein B. Methods In nmol/L: Risk-weighted apoB = apoB - Lp(a) + Lp(a) x 7 = apoB + Lp(a) x 6. Proportion of risk captured by apoB = apoB divided by risk-weighted apoB. Proportion of risk carried by Lp(a) = Lp(a) × 7 divided by risk-weighted apoB. Results Risk-weighted apoB agrees with risk estimation from large epidemiological studies and from several Mendelian randomization studies. Conclusions ApoB considerably underestimates risk in individuals with high Lp(a) levels. The association between apoB and incident CHD is diminished or even lost. These phenomena can be overcome and explained by risk-weighted apoB.

Background and aims: We 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. Methods: Using an extended biomarker dataset, we identified 47,362 participants with very low Lp(a) concentrations (

Background and aim: Many children with an FH mutation also exhibit elevated lipoprotein(a) levels, which is an independent risk factor for atherosclerotic cardiovascular disease. Studies have reported higher levels of lipoprotein(a) in adult and middle-aged women than men. There is limited knowledge on the concentration and change of lipoprotein(a) levels in children with genetic FH, and therefore we investigated sex-differences in lipoprotein(a) level and change in lipoprotein(a) in girls and boys with genetically confirmed FH. Methods: Medical records were reviewed retrospectively in 438 subjects with heterozygous FH that started follow-up below the age of 19 years at the Lipid Clinic, Oslo University Hospital in Norway, and of these we included 386 subjects with at least one Lp(a) measurement. Results: Mean (SD) age at baseline was 13.8 (7.3) years and the age was similar between sexes. Girls had a higher lipoprotein(a) level than boys at baseline: median (25–75 percentile) 223 (108–487) vs. 154 (78–360) mg/L, respectively (p 0.05). Conclusions: We found an increase in Lp(a) levels in children with genetic FH with age, and higher levels in girls than boys, which could impact risk assessment and future ASCVD. Further research is needed to elucidate whether subjects with FH could benefit from lipoprotein(a)-lowering therapies that are under current investigations.

Background: With the renewed interest in lipoprotein a (Lp(a)) shown by the European Atherosclerosis Society in relation to cardiovascular disease occurrence worldwide and especially in the South Asian population, its estimation once in a lifetime has been recommended (1–3). However, the role of this proatherogenic Lp(a) in regulating the severity of angiographic lesions in coronary artery disease (CAD) is poorly understood. This study aimed to correlate the serum Lp(a) level with angiographic lesion severity in subjects with CAD. Subjects and Methods: In this cross-sectional study, a total of 100 adult patients (mean age: 52.56 [±12.84] years, 84 [84%] males) with angiographically confirmed CAD were enrolled in a tertiary care hospital in Eastern India and their serum Lp(a) levels were estimated (by immunoassay method) and correlated with the SYNTAX score groups (33) and extent of disease – single-vessel disease (SVD), double-vessel disease (DVD), or triple-vessel disease (TVD). Results: Mean serum Lp(a) was elevated in the more severe disease group with SYNTAX >33 (88.79 mg/dl) than in lesser severity disease groups of SYNTAX 22-33 (57.07 mg/dl) and SYNTAX

Cardiovascular (CV) diseases are the leading causes of death worldwide in both sexes alike. However, there have been significant developments in CV pharmacotherapy, percutaneous intervention, and systems of care over the past three decades in parallel. Several landmark studies were presented and discussed in American Heart Association (AHA) 2023 Scientific Sessions held in Philadelphia. The dapagliflozin-myocardial infarction (MI) and SELECT discussed the CV benefits of newer antidiabetic drugs. The AZALEA-TIMI and ARTESIA evaluated newer anticoagulants in atrial fibrillation. VERVE-101 and LEPODISIRAN studies were related to lipid-lowering in clinical practice. The ESPRIT trial demonstrated the benefits of intensive blood lowering, while KARDIA-1 tested a new RNA-based therapeutic agent for blood pressure lowering. The MINT trial evaluated strategies for blood transfusion in anemia concomitant with acute MI. ORBITA-2 study demonstrated the positive impact of percutaneous coronary intervention for angina control in stable coronary artery disease. Hence, these studies encompassed almost all aspects of cardiology, including heart failure, acute coronary syndrome, lipidology, anticoagulation, hypertension, obesity, and coronary intervention.

Abstract Background Numerous 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. Methods Independent 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. Results Genetically 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). Conclusion Our 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.

Ruiming Wang, Weiguo Kong, Wenhua Zhang Department of Neurology, Hangzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, People’s Republic of ChinaCorrespondence: Wenhua Zhang, Department of Neurology, Hangzhou Traditional Chinese Medicine Hospital affiliated to Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, Tel +86-571-85827888, Fax +86-571-85119481, Email zwhzxpz@hotmail.comObjective: This study aimed to explore the relationship between serum lipoprotein(a) (LP(a)) levels and early neurological deterioration (END) in patients with acute ischemic stroke (AIS) after thrombolysis.Methods: In total, 236 patients with AIS after thrombolysis were enrolled in this study. Serum LP(a) levels were measured on admission after thrombolysis. END was defined as an increase of at least two points in the NIHSS score within 48 hours after thrombolysis. Binary logistic regression analysis was used to assess the association between serum LP(a) levels and END.Results: Overall, patients with END had higher LP(a) than those without END (high LP(a): 38.3% vs 22.2%, intermediate LP(a): 40.3% vs 41.8%, low LP(a): 21.3% vs 36.0%, p< 0.005). In the multivariate analysis, high LP(a) (defined as LP(a) level≥ 300 mg/L) was an independent risk factor for END post-thrombolysis (OR=3.154, 95% CI=1.067– 9.322, p=0.038).Conclusion: Our findings demonstrated that LP(a) was an independent risk factor for END post-thrombolysis and that LP(a) level≥ 300 mg/L could be associated with END post-thrombolysis in this study population.Keywords: Lipoprotein(a), early neurological deterioration, acute ischemic stroke, thrombolysis

Abstract Objective Serum lipoprotein(a) [Lp(a)] is a risk factor of cardiovascular diseases. However, the relationship between the serum Lp(a) and clinical outcomes has been seldom studied in Chinese hospitalized patients with cardiovascular diseases. Methods We retrospectively collected the clinical data of hospitalized patients with cardiovascular diseases in the Cardiovascular Department of Dongguan People’s Hospital from 2016 to 2021 through the electronic case system. Patients were divided into 4 groups based on Lp(a) quartiles: Quartile1 (≤ 80.00 mg/L), Quartile 2 (80.01 ~ 160.90 mg/L), Quartile 3 (160.91 ~ 336.41 mg/L), Quartile 4 (> 336.41 mg/L). Cox proportional hazard regression models were constructed to examine the relationship between Lp(a) and cardiovascular events. Results A total of 8382 patients were included in this study. After an average follow-up of 619 (320 to 1061) days, 1361 (16.2%) patients developed major adverse cardiovascular events, and 125 (1.5%) all-cause death were collected. The incidence of MACEs was 7.65, 8.24, 9.73 and 10.75 per 100 person-years in each Lp(a) quartile, respectively; the all-cause mortality was 0.48, 0.69, 0.64 and 1.18 per 100 person-years in each Lp(a) quartile, respectively. The multivariate Cox regression analysis suggested that high Lp(a) level was an independent risk factor for MACEs (HR: 1.189, [95% CI: 1.045 to 1.353], P = 0.030) and all-cause death (HR: 1.573, [95% CI: 1.009 to 2.452], P = 0.046). Conclusion In addition to traditional lipid indicators, higher Lp(a) exhibited higher risks of adverse cardiovascular events and death, indicated worse prognosis. Lp(a) may be a new target for the prevention of atherosclerotic diseases.

Motasim Jawi,1 Hadiah Bassam Al Mahdi,2,3 Hussam Daghistani,4,5 Yousef Almoghrabi,4,5 Rami Algahtani,6 Dalal Tawati,7 Mohammed R Algethami,8 Yasser Noorelahi,9 Zuhier Awan4 1Department of Physiology, College of Medicine, University of Jeddah, Jeddah, Saudi Arabia; 2Al Borg Medical Laboratories, Al Borg Diagnostics, Research and Development Unit, Jeddah, Saudi Arabia; 3Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; 4Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 5Regenerative Medicine Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; 6Department of Medicine, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; 7Department of Obstetrics and Gynecology, King Abdullah Medical Complex, Jeddah, Saudi Arabia; 8Department of Family and Community Medicine, College of Medicine, University of Jeddah, Jeddah, Saudi Arabia; 9Department of Radiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaCorrespondence: Motasim Jawi, Department of Physiology, College of Medicine, University of Jeddah, Jeddah, Saudi Arabia, Tel +966 569191939, Email mmjawi@uj.edu.saPurpose: Blood Lp(a) concentration is recognized as an independent risk factor for cardiovascular disease (CVD). Population-based lipoprotein(a) (Lp[a]) research in Saudi Arabia is rare. Thus, the primary goal of this pilot study was to identify age- and sex-specific reference ranges for Lp(a) levels, in addition to the associations between Lp(a) levels and other atherosclerotic markers in Saudi individuals.Patients and methods: A five-year retrospective study of Lp(a) and lipid markers in Saudi patients was conducted using the Al-Borg diagnostics database (2015– 2020). The population sample consisted of 361 Saudi individuals aged 18– 93 years (162 males, 199 females). An immunoturbidimetric technique was used to determine Lp(a) concentration.Results: The mean and median Lp(a) levels in the study population were 35 nmol/L and 50 nmol/L, respectively. Sex and age did not influence Lp(a) values. Lp(a) values showed a minor correlation with other atherosclerotic markers when the Pearson correlation coefficient was used. In Saudi Arabia, the distribution of Lp(a) concentrations is skewed to the left, favoring lower values.Conclusion: Lp(a) levels in individuals residing in Saudi Arabia were comparable to those observed in other ethnic groups. Additionally, standardizing Lp(a) measurements according to sex and age may enhance broader applicability and facilitate comparisons across different populations. However, larger studies are required to provide more comprehensive data for comparison.Keywords: lipoprotein(a), lipids, cardiovascular disease, reference range, reference interval, Saudi Arabia

Abstract Background There is evidence indicating that both lipoprotein(a) [Lp(a)] and fibrinogen (FIB) are associated with mortality, However, the impact of their combination on mortality has not been determined. Thus, the aim of this study was to examine the association between the combination of Lp(a) and FIB with all-cause and cause-specific mortality. Methods This prospective cohort study enrolled 4,730 participants from the third National Health and Nutrition Examination Survey. The exposure variables included Lp(a), FIB and their combination, while the outcome variables consisted of all-cause, cardiovascular disease (CVD) and cancer-related mortality. Multivariate COX regression, subgroup analysis, sensitivity analysis and restricted cubic spline (RCS) were used to investigate the association between Lp(a), FIB and their combination with all-cause, CVD and cancer-related mortality. Results Over a median follow-up period of 235 months, 2,668 individuals died, including 1,051 deaths attributed to CVD and 549 deaths due to cancer. Multivariate Cox regression analyses revealed independent associations between both Lp(a) and FIB with all-cause, CVD, and cancer-related mortality. Compared to participants in the 1st to 50th percentiles of both Lp(a) and FIB, those in the 90th to 100th percentiles exhibited multivariable adjusted HRs of 1.813 (95% CI: 1.419–2.317, P 0.05). Conversely, the relationship between Lp(a) and the risk of CVD-related mortality, as well as the relationship between FIB and the risk of all-cause and CVD-related mortality, were nonlinear (P for nonlinearity

Background: Retention of apolipoprotein B (apoB)-containing lipoproteins within the arterial wall plays a major causal role in atherosclerotic cardiovascular disease (ASCVD). There is a single apoB molecule in all apoB-containing lipoproteins. Therefore, quantitation of apoB directly estimates the number of atherogenic particles in plasma. ApoB is the preferred measurement to refine the estimate of ASCVD risk. Low-density lipoprotein (LDL) particles are by far the most abundant apoB-containing particles. In patients with elevated lipoprotein(a) (Lp(a)), apoB may considerably underestimate risk because Mendelian randomization studies have shown that the atherogenicity of Lp(a) is approximately 7-fold greater than that of LDL on a per apoB particle basis. In subjects with increased Lp(a), the association between LDL-cholesterol and incident CHD (coronary heart disease) is increased, but the association between apoB and incident CHD is diminished or even lost. Thus, there is a need to understand the mechanisms of Lp(a), LDL-cholesterol and apoB-related CHD risk and to provide clinicians with a simple practical tool to address these complex and variable relationships. How can we understand a patient's overall lipid-driven atherogenic risk? What proportion of this risk does apoB capture? What proportion of this risk do Lp(a) particles carry? To answer these questions, we created a novel metric of atherogenic risk: risk-weighted apolipoprotein B. Methods: In nmol/L: Risk-weighted apoB = apoB - Lp(a) + Lp(a) x 7 = apoB + Lp(a) x 6. Proportion of risk captured by apoB = apoB divided by risk-weighted apoB. Proportion of risk carried by Lp(a) = Lp(a) × 7 divided by risk-weighted apoB. Results: Risk-weighted apoB agrees with risk estimation from large epidemiological studies and from several Mendelian randomization studies. Conclusions: ApoB considerably underestimates risk in individuals with high Lp(a) levels. The association between apoB and incident CHD is diminished or even lost. These phenomena can be overcome and explained by risk-weighted apoB. [ABSTRACT FROM AUTHOR]

BACKGROUND: Despite the considerable progress made in preventative methods, medication, and interventional therapies, it remains evident that cardiovascular events (CVEs) continue to be the primary cause of both death and morbidity among individuals diagnosed with coronary artery disease (CAD). OBJECTIVE: To compare the connection between lipoprotein a (Lp[a]), fibrinogen (Fib), and both parameters combined with all-cause mortality to detect their value as prognostic biomarkers. METHODS: This is a retrospective study. Patients diagnosed with CAD between January 2007 and December 2020 at the Guangdong Provincial People's Hospital (China) were involved in the study. 43,367 patients met the eligibility criteria. The Lp(a) and Fib levels were distributed into three tertile groups (low, medium, and high). All of the patients included in the study were followed up for all-cause mortality. Kaplan–Meier and Cox regression were performed to determine the relationship between Lp(a), Fib, and all-cause mortality. A concordance statistics model was developed to detect the impact of Fib and Lp(a) in terms of anticipating poor outcomes in patients with CAD. RESULTS: Throughout a median follow-up of 67.0 months, 6,883 (15.9%) patients died. Participants with high Lp(a) (above 27.60 mg/dL) levels had a significantly higher risk for all-cause mortality than individuals with low Lp(a) levels (below 11.13 mg/dL; adjusted hazard ratio [aHR] 1.219, 95% confidence interval [CI]: 1.141–1.304, p < 0.001). Similarly, patients with high Fib levels (above 4.32 g/L) had a significantly greater risk of developing all-cause mortality compared with those with reduced Fib levels (below 3.41 g/L; aHR 1.415, 95% CI: 1.323–1.514, p < 0.001). Patients with raised Lp(a) and Fib levels had the maximum risk for all-cause mortality (aHR 1.702; 95% CI: 1.558–1.859, p < 0.001). When considered together, Lp(a) and Fib caused a significant elevation of the concordance statistic by 0.009 (p < 0.05), suggesting a higher value for predicting mortality when combining the two indicators. CONCLUSION: High Lp(a) and Fib levels could be used as predictive biomarkers for all-cause mortality in individuals with CAD. The prediction accuracy for all-cause mortality improved after combining the two parameters. [ABSTRACT FROM AUTHOR]

Background: Elevated levels of lipoprotein(a) [Lp(a)] represent a risk factor for cardiovascular disease including aortic valve stenosis, myocardial infarction and stroke. While the patho‐physiological mechanisms linking Lp(a) with atherosclerosis are not fully understood, from genetic studies that lower Lp(a) levels protect from CVD independently of other risk factors including lipids and lipoproteins. Hereby, Lp(a) has been considered an appealing pharmacological target. Results: However, approved lipid lowering therapies such as statins, ezetimibe or PCSK9 inhibitors have a neutral to modest effect on Lp(a) levels, thus prompting the development of new strategies selectively targeting Lp(a). These include antisense oligonucleotides and small interfering RNAs (siRNAs) directed towards apolipoprotein(a) [Apo(a)], which are in advanced phase of clinical development. More recently, additional approaches including inhibitors of Apo(a) and gene editing approaches via CRISPR‐Cas9 technology entered early clinical development. Conclusion: If the results from the cardiovascular outcome trials, designed to demonstrate whether the reduction of Lp(a) of more than 80% as observed with pelacarsen, olpasiran or lepodisiran translates into the decrease of cardiovascular mortality and major adverse cardiovascular events, will be positive, lowering Lp(a) will become a new additional target in the management of patients with elevated cardiovascular risk. [ABSTRACT FROM AUTHOR]

• About 2/3rd of surveyed providers do not regularly test for Lp(a) in their patients. • Underutilization of Lp(a) testing was seen across specialties including cardiology. • Lack of familiarity with Lp(a) was the most common reason cited for not testing. Guidelines recommend checking lipoprotein(a) [Lp(a)] levels in patients at high-risk for cardiovascular disease, with more recent recommendations advocating for universal screening in all adults. A brief electronic survey was distributed to select groups of University of Pennsylvania Health System (UPHS) providers, including Internal Medicine and Cardiology physicians and advance practice providers, to understand the current attitudes and barriers to testing for Lp(a). Of the 126 survey respondents, only 31% answered that they test for Lp(a) regularly in their practice. Presence of ASCVD and a family history of ASCVD were the most common reasons for testing. Most survey respondents (69%) replied that they do not currently check Lp(a) levels in patients. The most common reasons provided included lack of familiarity with Lp(a), insurance/ billing concerns, lack of clinical trial outcomes data, and lack of available pharmaceutical interventions. Results from ongoing clinical trials of novel Lp(a)-lowering therapies, if successful, may address provider hesitation toward Lp(a)-testing, but there remains a large gap to fill in awareness of Lp(a). [ABSTRACT FROM AUTHOR]

• Lp(a) assessment in patients with cardiovascular disease is low. • Hispanic and Black individuals are less likely to have Lp(a) tested compared to Whites. • Socioeconomic score and income impact Lp(a) ordering practices. High lipoprotein(a) [Lp(a)] levels are a risk factor for atherosclerotic cardiovascular disease (ASCVD), however Lp(a) ordering in clinical practice is low. This study examines how race/ethnicity and socioeconomic status influence Lp(a) ordering. This is a single center, retrospective study (2/1/2020-6/30/2023) using electronic medical records of adults with at least one personal ICD-10 diagnosis of ASCVD, aortic valve stenosis, resistant hypercholesterolemia (low-density lipoprotein cholesterol >160 mg/dL on statin therapy), and family history of ASCVD or high Lp(a). We evaluated Lp(a) level differences among racial/ethnic groups and sexes. We also assessed associations between diagnosis type, diagnosis number, age at diagnosis, race/ethnicity, socioeconomic score (based on zip codes), public health coverage and the presence of Lp(a) orders. 4% of our cohort (N=2,249 in 56,833) had an Lp(a) order (17.3% of whom identified as Hispanic, 8.7% non-Hispanic Black, 47.5% non-Hispanic White, and 27% Asian/other). Non-Hispanic Black and Hispanic patients had lower rates of Lp(a) orders (0.17% and 0.28%, respectively) when compared to non-Hispanic White patients (2.35%), p < 0.001, however, their median Lp(a) levels were higher, p < 0.001. Individuals on Medicaid or belonging to deprived socioeconomic groups were less likely to have an Lp(a) order (incidence rate ratio [IRR] = 0.40, p < 0.001 and IRR = 0.39, p < 0.001 respectively). Certain diagnosis (carotid stenosis, family history of ASCVD and familial hypercholesterolemia) and multiple diagnoses (>2) resulted in more Lp(a) orders compared to only one diagnosis (p < 0.001). Lp(a) ordering is low in patients with or at risk for ASCVD. Non-Hispanic Black and Hispanic patients are less likely to have an Lp(a) order. Individuals on Medicaid and residing in socioeconomically deprived neighborhoods are less likely to have an Lp(a) order. Lp(a) orders depend on the type and number of patients' diagnoses. [ABSTRACT FROM AUTHOR]

• Elevated lipoprotein(a) is an established risk factor for cardiovascular disease. • Lipoprotein apheresis is the only approved treatment to significantly lower lipoprotein(a). • Lipoprotein apheresis reduced the annual major adverse cardiac event (MACE) rate from 0.34 to 0.006 events per patient per year (98% reduction). Elevated lipoprotein(a) (Lp(a)) is an established risk factor for cardiovascular disease (CVD). To date, the only approved treatment to lower Lp(a) is lipoprotein apheresis (LA). Previous studies have demonstrated that LA is effective in reducing cardiovascular (CV) risk in patients with elevated low-density lipoprotein cholesterol (LDL-C) and/or Lp(a). Here we report our long-term experience with LA and its effectiveness in reducing CVD events in patients with elevated Lp(a). This retrospective open-label, single-center study included 25 individuals with Lp(a) elevation >60 mg/dL and LDL-C < 2.59 mmol/L who had indication for LA. The primary endpoint of this study was the incidence of any CV event (determined by medical records) after initiation of LA. Mean LA treatment duration was 7.1 years (min-max: 1–19 years). Median Lp(a) was reduced from 95.0 to 31.1 mg/dL after LA (-67.3%, p < 0.0001). Mean LDL-C was reduced from 1.85 to 0.76 mmol/L after LA (-58.9%, p < 0.0001). Prior to LA, 81 CV events occurred in total (0.87 events/patient/year). During LA, 49 CV events occurred in total (0.24 events/patient/year; -0.63, p = 0.001). Yearly major adverse cardiac event (MACE) rate was reduced from 0.34 to 0.006 (-0.33, p = 0.0002). Similar results were obtained when considering only individuals with baseline LDL-C below 1.42 mmol/L. In this observational study of a heterogeneous CV high-risk cohort with elevated Lp(a), LA reduced Lp(a) levels and was paralleled by a decrease in CV events and MACE. We recommend LA for patients with high Lp(a) who still have CV events despite optimal lipid-lowering medication and lifestyle changes. [ABSTRACT FROM AUTHOR]

• A significant joint association of Lp(a) and Lp-PLA2 with the risk of stroke recurrence was observed. • Patients with concomitant presence of elevated Lp(a) and Lp-PLA2 have greater risk of stroke recurrence. • Both significant multiplicative and additive interaction were observed between Lp(a) and Lp-PLA2. Currently little is known about the joint association of lipoprotein (a) [Lp(a)] and lipoprotein-associated phospholipase A2 (Lp-PLA2) with stroke recurrence. In this prospective multicenter cohort study, 10,675 consecutive acute ischemic stroke (IS) and transient ischemic attack (TIA) patients with Lp(a) and Lp-PLA2 were enrolled. The association of stroke recurrence within 1 year with Lp(a) and Lp-PLA2 was assessed using Cox proportional hazards models and Kaplan-Meier curves. The interaction between Lp(a) and Lp-PLA2 with stroke recurrence was evaluated by multiplicative and additive scales. A significant joint association of Lp(a) and Lp-PLA2 with the risk of stroke recurrence was observed. Multivariate Cox regression analysis demonstrated that the combination of elevated Lp(a) (≥ 50 mg/dL) and Lp-PLA2 (≥175.1 ng/mL) was independently associated with the risk of stroke recurrence (adjusted hazard ratio: 1.42; 95% confidence interval [CI]: 1.15–1.76). Both significant multiplicative [(exp(β3): 1.63, 95% CI: 1.17–2.29, P = 0.004] and additive interaction (RERI: 0.55, 95% CI: 0.20–0.90, P = 0.002; AP: 0.39, 95% CI, 0.24–0.53) were observed between Lp(a) and Lp-PLA2. Our results indicated that Lp(a) and Lp-PLA2 have a joint association with the risk of stroke recurrence in IS/TIA patients. Patients with concomitant presence of elevated Lp(a) and Lp-PLA2 have greater risk of stroke recurrence. [ABSTRACT FROM AUTHOR]

Aims Lipoprotein(a) [Lp(a)] levels are predominantly genetically determined and repeat measurements are generally considered unlikely to be clinically useful. However, the temporal variation of Lp(a) is not well characterized. Our aim was to determine the intra-individual variability of Lp(a) and whether a repeated measure reclassified Lp(a)-specific cardiovascular risk using the European Atherosclerosis Society (EAS) consensus statement risk categories. Methods and results This retrospective cohort study analysed initial and repeated serum Lp(a) levels measured using the same methodology from 609 individuals in the Nashville Biosciences database, a de-identified electronic medical records database. Baseline and follow-up paired values were significantly different (P < 0.05), with an absolute change of ≥10 mg/dL in 38.1% [95% CI 34.2–42%] and a >25% change in 40.5% [95% CI 36.6–44.3%] of individuals. Although the categories of those whose values were in the EAS low-risk and high-risk categories did not change, 53% of those in the intermediate 'grey-zone' category transitioned to either the low-risk (20%) or high-risk (33%) category. Black individuals exhibited greater variability than White individuals and women exhibited greater variability than men. There was a positive correlation between the baseline Lp(a) levels and the absolute changes in Lp(a), (r = 0.59, P < 0.01). Conclusion Temporal-related changes in Lp(a) variability were present in many individuals. A repeat Lp(a) measure may allow more precise Lp(a)-specific cardiovascular risk prediction for individuals whose initial value is in the EAS-defined intermediate 'grey-zone' category. Lp(a) variability should be included in calculating the expected effect sizes in future clinical research studies targeting Lp(a). [ABSTRACT FROM AUTHOR]

Background: Lipoprotein(a) [Lp(a)] plasma level is a well‐known risk factor for coronary artery disease (CAD). Existing data regarding the influence of sex on the Lp(a)‐CAD relationship are inconsistent. Objective: To investigate the relationship between Lp(a) and CAD in men and women and to elucidate any sex‐specific differences that may exist. Methods: Data of patients with Lp(a) measurements who were admitted to a tertiary university hospital, Koc University Hospital, were analyzed. The relationship between Lp(a) levels and CAD was explored in all patients and in subgroups created by sex. Two commonly accepted Lp(a) thresholds ≥ 30 and ≥ 50 mg/dL were analyzed. Results: A total of 1858 patients (mean age 54 ± 17 years; 53.33% females) were included in the analysis. Lp(a) was an independent predictor of CAD according to the multivariate regression model for the entire cohort. In all cohort, both cut‐off values (≥ 30 and ≥ 50 mg/dL) were detected as independent predictors of CAD (p < 0.001). In sex‐specific analysis, an Lp(a) ≥ 30 mg/dL was an independent predictor of CAD only in women (p < 0.001), but Lp(a) ≥ 50 mg/dL was a CAD predictor both in men and women (men, p = 0.004; women, p = 0.047). Conclusion: The findings of this study may suggest that different thresholds of Lp(a) level can be employed for risk stratification in women compared to men. [ABSTRACT FROM AUTHOR]

Background: Numerous 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. Methods: Independent 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. Results: Genetically 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). Conclusion: Our 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. [ABSTRACT FROM AUTHOR]