High lipoprotein(a) is a risk factor for peripheral artery disease, abdominal aortic aneurysms, and major adverse limb events.

PURPOSE OF REVIEW: To summarize evidence from recent studies of high lipoprotein(a) as a risk factor for peripheral artery disease (PAD), abdominal aortic aneurysms (AAA), and major adverse limb events (MALE). Additionally, provide clinicians with 10-year absolute risk charts enabling risk prediction of PAD and AAA by lipoprotein(a) levels and conventional risk factors. RECENT FINDINGS: Numerous studies support high lipoprotein(a) as an independent risk factor for PAD, AAA, and MALE. The strongest evidence is from the Copenhagen General Population Study (CGPS) and the UK Biobank, two large general population-based cohorts. In the CGPS, a 50 mg/dl higher genetically determined lipoprotein(a) associated with hazard ratios of 1.39 (1.24-1.56) for PAD and 1.21 (1.01-1.44) for AAA. Corresponding hazard ratio in the UK Biobank were 1.38 (1.30-1.46) and 1.42 (1.28-1.59). In CGPS participants with levels at least 99th (≥143 mg/dl) vs, less than 50th percentile (≤9 mg/dl), hazard ratios were 2.99 (2.09-4.30) for PAD and 2.22 (1.21-4.07) for AAA, with a corresponding incidence rate ratio for MALE of 3.04 (1.55-5.98) in participants with PAD. SUMMARY: Evidence from both observational and genetic studies support high lipoprotein(a) as a causal risk factor for PAD, AAA, and MALE, and highlight the potential of future lipoprotein(a)-lowering therapy to reduce the substantial morbidity and mortality associated with these diseases.

Lipoprotein(a) is a highly atherogenic lipoprotein: pathophysiological basis and clinical implications.

PURPOSE OF REVIEW: Lipoprotein(a) has been identified as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. However, as reviewed here, there is ongoing debate as to the key pathogenic features of Lp(a) particles and the degree of Lp(a) atherogenicity relative to low-density lipoprotein (LDL). RECENT FINDINGS: Genetic analyses have revealed that Lp(a) on a per-particle basis is markedly (about six-fold) more atherogenic than LDL. Oxidized phospholipids carried on Lp(a) have been found to have substantial pro-inflammatory properties triggering pathways that may contribute to atherogenesis. Whether the strength of association of Lp(a) with ASCVD risk is dependent on inflammatory status is a matter of current debate and is critical to implementing intervention strategies. Contradictory reports continue to appear, but most recent studies in large cohorts indicate that the relationship of Lp(a) to risk is independent of C-reactive protein level. SUMMARY: Lp(a) is a highly atherogenic lipoprotein and a viable target for intervention in a significant proportion of the general population. Better understanding the basis of its enhanced atherogenicity is important for risk assessment and interpreting intervention trials.

ADLM Guidance Document on the Measurement and Reporting of Lipids and Lipoproteins.

BACKGROUND: The accurate measurement of blood lipids and lipoproteins is crucial for the clinical management of atherosclerotic disease risk. Despite progress in standardization, there are still significant variations in pre-analytical requirements, methods, nomenclature, and reporting work flows. CONTENT: The guidance document aims to improve standardization of clinical lipid testing work flows. It provides recommendations for the components of the lipid panel, fasting requirements, reporting of results, and specific recommendations for non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], apolipoprotein B (apo B), point-of-care lipid testing, and LDL subfraction testing. SUMMARY: Lipid panels should always report non-HDL-C and LDL-C calculations if possible. Fasting is not routinely required except in specific cases. Modern equations should be utilized for LDL-C calculation. These equations allow for LDL-C reporting at elevated concentrations of triglycerides and obviate the need for direct measured LDL-C in most cases.

Is lipoprotein(a) measurement important for cardiovascular risk stratification in children and adolescents?

BACKGROUND: Elevated lipoprotein (Lp(a)) levels are associated with increased risk of atherosclerotic processes and cardiovascular events in adults. The amount of Lp(a) is mainly genetically determined. Therefore, it is important to identify individuals with elevated Lp(a) as early as possible, particularly if other cardiovascular risk factors are present. The purpose of the study was to investigate whether, in a population of children and adolescents already followed for the presence of one or more cardiovascular risk factors (elevated blood pressure (BP), and/or excess body weight, and/or dyslipidemia), the measurement of Lp(a) can be useful for better stratifying their risk profile. METHODS: In a sample of 195 children and adolescents, height, body weight, waist circumference and systolic (SBP) and diastolic (DBP) BP were measured. Body Mass Index (BMI) and SBP and DBP z-scores were calculated. Plasma Lp(a), total cholesterol, high-density lipoprotein (HDL), triglycerides, glucose, insulin, uric acid and creatinine were assessed. Low-density lipoprotein (LDL) cholesterol was calculated with the Friedewald formula. High Lp(a) was defined as ≥ 75 nmol/L and high LDL cholesterol as ≥ 3.37 mmol/L. RESULTS: Our sample of children and adolescents (54.4% males, mean age 11.5 years) had median LDL cholesterol and Lp(a) values equal to 2.54 (interquartile range, IQR: 2.07-3.06) mmol/L and 22 (IQR: 7.8-68.6) nmol/L respectively. 13.8% of children had LDL cholesterol ≥ 3.37 mmol/L and 22.6 Lp(a) values ≥ 75 nmol/L. Lp(a) values were higher in children of normal weight than in those with excess weight (p = 0.007), but the difference disappeared if normal weight children referred for dyslipidemia only were excluded from the analysis (p = 0.210). 69.4% of children had normal Lp(a) and LDL cholesterol values and only 6.2% showed both elevated Lp(a) and LDL cholesterol levels. However, 16.6% of the sample, despite having normal LDL cholesterol, had elevated Lp(a) values. Multivariable analyses showed a significant association of LDL cholesterol both with Lp(a) values, and with the presence of elevated Lp(a) levels. For each mmol/L increase in LDL cholesterol the risk of having an elevated Lp(a) value increased by 73%. There was an inverse correlation between BMI z-score and Lp(a). Neither BP z-scores, nor other biochemical parameters were associated with Lp(a). CONCLUSIONS: In our population more than one out of five children had elevated Lp(a) values, and in about 17% of children elevated Lp(a) values were present in the absence of increased LDL cholesterol. Our results suggest that Lp(a) measurement can be useful to better define the cardiovascular risk profile in children and adolescents already followed for the presence of other cardiovascular risk factors such as elevated BP, excess body weight and high LDL cholesterol.

Lipoprotein(a) and cardiovascular disease.

Elevated plasma levels of lipoprotein(a) (Lp(a)) are a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Lp(a) consists of a lipoprotein particle resembling low density lipoprotein and the covalently-attached glycoprotein apolipoprotein(a) (apo(a)). Novel therapeutics that specifically and potently lower Lp(a) levels are currently in advanced stages of clinical development, including in large, phase 3 cardiovascular outcomes trials. However, fundamental unanswered questions remain concerning some key aspects of Lp(a) biosynthesis and catabolism as well as the true pathogenic mechanisms of the particle. In this review, we describe the salient biochemical features of Lp(a) and apo(a) and how they underlie the disease-causing potential of Lp(a), the factors that determine plasma Lp(a) concentrations, and the mechanism of action of Lp(a)-lowering drugs.

The Burden of Lipoprotein (a) in Türkiye: What We Know and What We Need to Learn.

Lipoprotein (a) is a well-known cardiovascular risk factor, and its level is primarily determined genetically. Because of its genetic basis, average Lipoprotein (a) levels may vary between different populations. In Türkiye, the average Lipoprotein (a) level remains uncertain due to the limited number of large population studies. Herein, we aimed to provide an overview of Türkiye's average Lipoprotein (a) levels by reviewing data from the available studies on Lipoprotein (a) in the Turkish population.

Lipoprotein(a) level predicts the development of nonalcoholic fatty liver disease in Korean adults: A retrospective longitudinal study.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent condition in the general population. Although recent studies have demonstrated a link between NAFLD and lipoprotein(a), a low-density lipoprotein-like particle synthesized in the liver, its precise physiological role and mechanism of action remain unclear. This study aimed to investigate the relationship between lipoprotein(a) levels and development of NAFLD and hepatic fibrosis in Korean adults. A total of 1501 subjects who underwent abdominal ultrasonography at least twice as part of a health checkup program were enrolled. Biochemical and ultrasonography results were analyzed longitudinally, and the degree of hepatic fibrosis was calculated in subjects with NAFLD using serum biomarkers, such as fibrosis-4 (FIB-4). During the 3.36-year follow-up period, 352 patients (23.5%) were diagnosed with NAFLD. The subjects were categorized into 4 groups based on their lipoprotein(a) levels. Remarkably, the incidence of NAFLD decreased as the lipoprotein(a) levels increased. Following logistic regression analysis and adjustment for various risk factors, the odds ratio for the development of NAFLD was 0.625 (95% CI 0.440-0.888; P = .032) when comparing the highest to the lowest tertile of lipoprotein(a). However, no significant association was observed between the occurrence of hepatic fibrosis and lipoprotein(a) levels in subjects with NAFLD. Lipoprotein(a) levels have been identified as a significant predictor of NAFLD development. Additional large-scale studies with extended follow-up periods are required to better understand the effect of lipoprotein(a) on NAFLD and hepatic fibrosis.

Lipoprotein(a) in interventional cardiology: identifying patients at highest risk of recurrent cardiovascular events through early recognition - a case based review.

INTRODUCTION: Lipoprotein(a) [Lp(a)] is linked to higher risks of atherosclerotic cardiovascular disease (ASCVD). Current guideline recommendations are quite liberal on measuring Lp(a) (Class IIa, Level C), and may lead to underuse among (interventional) cardiologists. AREAS COVERED: This case-based narrative review outlines four clinical cases of patients with elevated Lp(a) to illustrate its pathophysiological impact on coronary artery disease (CAD). The expert consensus statements from the American Heart Association (AHA) and European Atherosclerosis Society (EAS) served as the basis of this review. More recent publications, from 2023 to 2024, were accessed through the MEDLINE online library. EXPERT OPINION: We highlighted the importance of routine Lp(a) measurement in identifying patients at high risk for atherosclerosis, necessitating potent risk mitigation. Measuring Lp(a) helps clinicians identify which patients are at highest residual risk, who require potent pharmacological treatment and special attention during catheter interventions. As noninvasive and advanced intravascular imaging modalities evolve, future catheterization laboratories will integrate advanced imaging, diagnostics, and treatment, facilitating tailored patient care. Knowing Lp(a) levels is crucial in this context. While Lp(a)-lowering drugs are currently investigated in clinical trials, it is of paramount importance to know Lp(a) levels and strive toward aggressive management of other modifiable risk factors in patients with elevated Lp(a) and established symptomatic CAD being diagnosed or treated in catheterization laboratories.

Is There a Need for Sex-Tailored Lipoprotein(a) Cut-Off Values for Coronary Artery Disease Risk Stratification?

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.

Lipoprotein(a) and cardiovascular disease.

One in five people are at high risk for atherosclerotic cardiovascular disease and aortic valve stenosis due to high lipoprotein(a). Lipoprotein(a) concentrations are lowest in people from east Asia, Europe, and southeast Asia, intermediate in people from south Asia, the Middle East, and Latin America, and highest in people from Africa. Concentrations are more than 90% genetically determined and 17% higher in post-menopausal women than in men. Individuals at a higher cardiovascular risk should have lipoprotein(a) concentrations measured once in their lifetime to inform those with high concentrations to adhere to a healthy lifestyle and receive medication to lower other cardiovascular risk factors. With no approved drugs to lower lipoprotein(a) concentrations, it is promising that at least five drugs in development lower concentrations by 65-98%, with three currently being tested in large cardiovascular endpoint trials. This Review covers historical perspectives, physiology and pathophysiology, genetic evidence of causality, epidemiology, role in familial hypercholesterolaemia and diabetes, management, screening, diagnosis, measurement, prevention, and future lipoprotein(a)-lowering drugs.

Lipoprotein(a) and risk-weighted apolipoprotein B: a novel metric for atherogenic risk.

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.

Elevated High-Sensitivity C-Reactive Protein Level Enhances the Impact of Lipoprotein(a) on Platelet Reactivity in PCI Patients Treated with Clopidogrel.

BACKGROUND: Recently, the effect of Lipoprotein(a) [Lp(a)] on thrombogenesis has aroused great interest, while inflammation has been reported to modify the Lp(a)-associated risks through an unidentified mechanism. PURPOSE: This study aimed to evaluate the association between platelet reactivity with Lp(a) and high-sensitivity C-reactive protein (hs-CRP) levels in percutaneous intervention (PCI) patients treated with clopidogrel. METHODS: Data were collected from 10,724 consecutive PCI patients throughout the year 2013 in Fuwai Hospital. High on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) were defined as thrombelastography (TEG) maximum amplitude of adenosine diphosphate-induced platelet (MAADP) > 47 mm and < 31 mm, respectively. RESULTS: 6615 patients with TEG results were finally enrolled. The mean age was 58.24 ± 10.28 years and 5131 (77.6%) were male. Multivariable logistic regression showed that taking Lp(a) < 30 mg/dL and hs-CRP < 2 mg/L as the reference, isolated Lp(a) elevation [Lp(a) ≥ 30 mg/dL and hs-CRP < 2 mg/L] was not significantly associated with HTPR (P = 0.153) or LTPR (P = 0.312). However, the joint elevation of Lp(a) and hs-CRP [Lp(a) ≥ 30 mg/dL and hs-CRP ≥ 2 mg/L] exhibited enhanced association with both HTPR (OR:1.976, 95% CI 1.677-2.329) and LTPR (OR:0.533, 95% CI 0.454-0.627). CONCLUSIONS: The isolated elevation of Lp(a) level was not an independent indicator for platelet reactivity, yet the concomitant elevation of Lp(a) and hs-CRP levels was significantly associated with increased platelet reactivity. Whether intensified antiplatelet therapy or anti-inflammatory strategies could mitigate the risks in patients presenting combined Lp(a) and hs-CRP elevation requires future investigation.

Assessment of Lipoprotein (a) Levels in Patients with Atherosclerotic Cardiovascular Disease: Single Center Experience from Türkiye.

OBJECTIVE: This study aims to evaluate the role of elevated lipoprotein (a) [Lp(a)] levels as a potential contributor to residual risk in individuals with atherosclerotic cardiovascular disease (ASCVD). Considering that approximately 90% of Lp(a) levels are genetically determined and can vary regionally, we assessed Lp(a) levels in a cohort of ASCVD patients from the Turkish population, where data is currently limited. METHODS: We conducted a retrospective analysis of data and Lp(a) measurements collected from individuals diagnosed with ASCVD at a single center. RESULTS: The analysis included Lp(a) levels of 1193 consecutive individuals. The mean Lp(a) level was 28.2 mg/dL, with a median of 16 mg/dL and an interquartile range (IQR) from the 25th to the 75th percentile, 7 mg/dL to 39 mg/dL. The highest recorded Lp(a) level was 326 mg/dL. Among the cases, 18.7% exhibited Lp(a) levels ≥ 50 mg/dL, 10.8% had levels ≥ 70 mg/dL, and 5.8% had levels ≥ 90 mg/dL. The mean levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were 132 ± 47 mg/dL and 212 ± 54 mg/dL, respectively. Lp(a) levels were significantly higher in females compared to males. Furthermore, the proportion of females with Lp(a) levels ≥ 90 mg/dL was higher than in males (11.4% vs. 1.4%; P < 0.01). Additionally, a modest but significant correlation was observed between Lp(a) levels and TC (r = 0.075, P = 0.01) as well as LDL-C (r = 0.106, P < 0.01). CONCLUSION: This study revealed that Lp(a) concentrations were higher in women and statin users among ASCVD patients and identified a weak but significant correlation between Lp(a) levels and both TC and LDL-C.

The Off-Treatment Effects of Olpasiran on Lipoprotein(a) Lowering: OCEAN(a)-DOSE Extension Period Results.

BACKGROUND: Olpasiran, a small interfering RNA (siRNA), blocks lipoprotein(a) (Lp(a)) production by preventing translation of apolipoprotein(a) mRNA. In phase 2, higher doses of olpasiran every 12 weeks (Q12W) reduced circulating Lp(a) by >95%. OBJECTIVES: This study sought to assess the timing of return of Lp(a) to baseline after discontinuation of olpasiran, as well as longer-term safety. METHODS: OCEAN(a)-DOSE (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study) was a phase 2, dose-finding trial that enrolled 281 participants with atherosclerotic cardiovascular disease and Lp(a) >150 nmol/L to 1 of 4 active doses of olpasiran vs placebo (10 mg, 75 mg, 225 mg Q12W, or an exploratory dose of 225 mg Q24W given subcutaneously). The last dose of olpasiran was administered at week 36; after week 48, there was an extended off-treatment follow-up period for a minimum of 24 weeks. RESULTS: A total of 276 (98.2%) participants entered the off-treatment follow-up period. The median study exposure (treatment combined with off-treatment phases) was 86 weeks (Q1-Q3: 79-99 weeks). For the 75 mg Q12W dose, the off-treatment placebo-adjusted mean percent change from baseline in Lp(a) was -76.2%, -53.0%, -44.0%, and -27.9% at 60, 72, 84, and 96 weeks, respectively (all P < 0.001). The respective off-treatment changes in Lp(a) for the 225 mg Q12W dose were -84.4%, -61.6%, -52.2%, and -36.4% (all P < 0.001). During the extension follow-up phase, no new safety concerns were identified. CONCLUSIONS: Olpasiran is a potent siRNA with prolonged effects on Lp(a) lowering. Participants receiving doses ≥75 mg Q12W sustained a ∼40% to 50% reduction in Lp(a) levels close to 1 year after the last dose. (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study [OCEAN(a)-DOSE]; NCT04270760).

Atherogenic lipid profile in patients with statin treatment after acute coronary syndrome: a real-world analysis from Chinese cardiovascular association database.

BACKGROUND: Adverse atherogenic lipid profile is associated with an increased risk of major adverse cardiac events in patients after acute coronary syndrome (ACS). Knowledge regarding the impact of statins on lipid profile remains limited. METHODS: We retrospectively analysed multicenter, real-world data from the Chinese Cardiovascular Association Database-iHeart Project. Patients with a primary diagnosis of ACS from 2014 to 2021 during index hospitalisation and having at least one lipid panel record after discharge within 12 months were enrolled. We analysed target achievement of atherogenic lipid profile, including apolipoprotein B (< 80 mg/dL), low-density lipoprotein cholesterol (LDL-C) (< 1.8 mmol/L), lipoprotein(a) [Lp(a)] (< 30 mg/dL), triglycerides (< 1.7 mmol/L), remnant cholesterol (RC) (< 0.78 mmol/L), non-high-density lipoprotein cholesterol (< 2.6 mmol/L) at baseline and follow-up. Multivariate Cox regression models were employed to investigate the association between patient characteristics and target achievement. RESULTS: Among 4861 patients, the mean age was 64.9 years. Only 7.8% of patients had all atherogenic lipids within the target range at follow-up. The proportion of target achievement was for LDL-C 42.7%, Lp(a) 73.3%, and RC 78.5%. Patients with female sex, younger age, myocardial infarction, hypertension, and hypercholesteremia were less likely to control LDL-C, Lp(a), and RC. An increase in the burden of comorbidities was negatively associated with LDL-C and Lp(a) achievements but not with RC. CONCLUSIONS: A substantial gap exists between lipid control and the targets recommended by contemporary guidelines. Novel therapeutics targeting the whole atherogenic lipid profile will be warranted to improve cardiovascular outcomes.

Elderly patients with very high plasma lipoprotein(a) concentrations and few cardiovascular consequences: a case series.

Lipoprotein(a) (Lp(a)) is an atherogenic low-density lipoprotein (LDL)-like particle that is currently regarded as a non-modifiable risk factor for atherosclerotic cardiovascular disease. The number of patients detected with elevated Lp(a) concentrations has been increasing in recent years, although the implication of this finding is unclear for patients and physicians. We screened our lipid clinic database for patients aged >65 years with very high Lp(a) concentrations, which were defined as >230 nmol/L, and cardiovascular outcomes were assessed. The patients' (n = 16) mean (±standard deviation) age was 72.2 ± 7.1 years and the mean Lp(a) concentration was 313 ± 68 nmol/L. After a cumulative 129.0 patient-year follow-up (mean: 8.1 ± 4.2 years), the mean age was 80.3 ± 7.0 years. We observed a low baseline prevalence of cardiovascular events, with only two patients having a history of cardiovascular events. Furthermore, zero incident adverse cardiovascular events were recorded over the follow-up. Therefore, very high Lp(a) concentrations and disease-free old age are not mutually exclusive. Our aggregated clinical experience is that there is only a modest association between elevated Lp(a) concentrations and adverse outcomes. Nonetheless, we still advise treating modifiable risk factors in these patients.

Lipoprotein(a) in Children and Adolescents: Risk or Causal Factor for Cardiovascular Disease? A Narrative Review.

The evaluation of serum Lp(a) values in childhood and adolescence has been widely debated, and in the last few years, many authors have tried to better define Lp(a) role in atherosclerosis pathogenesis, starting from childhood. In our narrative review, we have evaluated the main historical stages of Lp(a) studies in childhood, trying to focus on pathogenic mechanisms linked to elevated serum Lp(a) values, starting from ischemic stroke and vascular damage, and to its possible direct involvement in premature atherosclerosis from childhood onwards. Historic manuscripts on Lp(a) in pediatric patients have mainly focused on serum Lp(a) values and increased stroke risk. More recently, many studies have evaluated Lp(a) as a coronary vascular disease (CVD) risk factor starting from childhood, especially related to a positive family history of premature CVD. Finally, only a few studies evaluated the role of Lp(a) in premature atherosclerotic processes and endothelial and vascular damage in pediatric patients. Lastly, we have hypothesized a future perspective, with the hope that plasma Lp(a) levels will be treated with a tailored pharmacologic approach, and Lp(a) will become a precocious therapeutic target to control the atherosclerotic pathways from the first years of life.

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

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 (ß = - 0.15, SE = 0.05, P = 0.003). The sensitivity analysis revealed that WME (ß = - 0.26, SE = 0.07, P = 0.0002), but not MR‒Egger (ß = - 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.

Aspirin use in patients with elevated lipoprotein(a): Impact on cardiovascular events and bleeding.

The role of aspirin in cardiovascular primary prevention remains controversial. There are physiological reasons to explore its potential benefits in patients with high levels of lipoprotein(a) [Lp(a)], mainly due to its antifibrinolytic properties and interactions with platelets. The primary objective of this systematic review was to evaluate the cardiovascular benefits and bleeding risks associated with aspirin use in patients who have elevated Lp(a) levels but no history of cardiovascular disease. This systematic review was conducted following PRISMA guidelines. We performed a literature search to identify studies assessing the cardiovascular benefits and bleeding risks of aspirin use in patients with elevated Lp(a) levels (or a related genetic variant) who have no history of cardiovascular disease. Five studies (49,871 individuals) were considered for this systematic review. Three studies assessed the impact of aspirin use in relation to genetic variants associated with elevated Lp(a) levels (SNP rs379822), while the remaining two studies directly measured plasma levels of Lp(a). The endpoints evaluated varied among the studies. Overall, the findings consistently show that carriers of the apolipoprotein(a) variant or patients with Lp(a) levels > 50 mg/dL experience a reduction in cardiovascular risk with aspirin use. No significant bleeding issues were observed, although such events were reported in only two studies. This systematic review suggests that aspirin use in patients with elevated Lp(a) levels and no prior cardiovascular history may reduce cardiovascular risk. The available data on bleeding risk is insufficient.