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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.

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.

Abstract 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 (

Lipoprotein (a) (Lp(a)) is a risk factor for cardiovascular diseases and mainly regulated by the complex LPA gene. We investigated the types of variation in the LPA gene and their predictive performance on Lp(a) concentration. We determined the Kringle IV-type 2 (KIV-2) copy number (CN) using the DRAGEN LPA Caller (DLC) and a read depth-based CN estimator in 8351 short-read whole genome sequencing samples from the GENESIS-HD study. The pentanucleotide repeat in the promoter region was genotyped with GangSTR and ExpansionHunter. Lp(a) concentration was available in 4861 population-based subjects. Predictive performance on Lp(a) concentration was investigated using random forests. The agreement of the KIV-2 CN between the two specialized callers was high (r = 0.9966; 95% confidence interval [CI] 0.9965–0.9968). Allele-specific KIV-2 CN could be determined in 47.0% of the subjects using the DLC. Lp(a) concentration can be better predicted from allele-specific KIV-2 CN than total KIV-2 CN. Two single nucleotide variants, 4925G>A and rs41272114C>T, further improved prediction. The genetically complex LPA gene can be analyzed with excellent agreement between different callers. The allele-specific KIV-2 CN is more important for predicting Lp(a) concentration than the total KIV-2 CN.

Abstract High lipoprotein(a) (Lp(a)) levels are associated with an increased risk of arterial hypertension (AHT) and atherosclerotic cardiovascular disease. However, little is known about the detailed profile of AHT based on Lp(a) levels. This observational study focused on elucidating the relationship between Lp(a) concentrations and specific indices obtained from 24-h ambulatory blood pressure (BP) monitoring in hypertensive patients over 18 years of age. We gathered and analyzed data on BP indices along with demographic, epidemiological, clinical, and laboratory variables from 227 hypertensive patients, median age 56 years, including 127 women (56%). After comparing hypertensive patients with Lp(a) levels above and below 125 nmol/L, we found that a 10 mmHg increase in nocturnal systolic BP and all pulse pressure indices (24-h, daytime, and night-time) was associated with an increased risk of high Lp(a) levels by more than 20% and 40%, respectively. Similarly, each 10% increase in the area under the function over time of nocturnal diastolic BP dipping was associated with more than a 30% decrease in the odds of belonging to the elevated Lp(a) levels category. Additionally, Lp(a) levels above 125 nmol/L were associated with higher 24-h, daytime, and night-time systolic BP and pulse pressure load. The relationship between Lp(a) and AHT appears to extend beyond conventional BP measurements, which may be relevant given the prognostic implications of nocturnal BP and pulse pressure indices.

Introduction Blood lipoprotein(a) (Lp(a)) levels have been observed to be inversely correlated with type 2 diabetes (T2D). In this Mendelian randomization (MR) study, the causal impact of genetically predicted Lp(a) on T2D was assessed. Methods A two-sample MR analysis was conducted. Data were obtained from UK Biobank and FinnGen consortia. Primary analysis was based on an inverse-variance-weighted mean (IVM) approach. Results No statistically significant association between the genetically predicted levels of Lp(a) and T2D was detected (p = 0.362) in IVM analysis involving data of 563,420 patients. Conclusions Genetically predicted Lp(a) concentration does not appear to be causally related to the risk of T2D.

Lipoprotein(a) [Lp(a)] is made up of a low-density lipoprotein (LDL) particle and a specific apolipoprotein(a). The blood concentration of Lp(a) is approximately 90% genetically determined, and the main genetic factor determining Lp(a) levels is the size of the apo(a) isoform, which is determined by the number of KIV2 domain repeats. The size of the apo(a) isoform is inversely proportional to the blood concentration of Lp(a). Lp(a) is a strong and independent cardiovascular risk factor. Elevated Lp(a) levels ≥ 50 mg/dl (≥ 125 nmol/l) are estimated to occur in more than 1.5 billion people worldwide. However, determination of Lp(a) levels is performed far too rarely, including Poland, where, in fact, it is only since the 2021 guidelines of the Polish Lipid Association (PoLA) and five other scientific societies that Lp(a) measurements have begun to be performed. Determination of Lp(a) concentrations is not easy due to, among other things, the different sizes of the apo(a) isoforms; however, the currently available certified tests make it possible to distinguish between people with low and high cardiovascular risk with a high degree of precision. In 2022, the first guidelines for the management of patients with elevated lipoprotein(a) levels were published by the European Atherosclerosis Society (EAS) and the American Heart Association (AHA). The first Polish guidelines are the result of the work of experts from the two scientific societies and their aim is to provide clear, practical recommendations for the determination and management of elevated Lp(a) levels.

Background: The clinical phenotype of familial hypercholesterolemia (FH) combined with the classical genetic defects of this disease increase the risk of coronary artery disease (CAD) in the case of a high level of lipoprotein (a) (Lp(a)). Aim: To assess the association of hereditary disorders of lipid metabolism with a high level of Lp(a) in the case of an early manifestation of CAD in the absence of the FH phenotype. Methods: We studied 81 patients with premature CAD (at the age up to 55 years in men and up to 60 years in women). Lp(a) was measured in the blood serum by the immunoturbidimetric method. We performed the molecular genetic testing, using massively parallel sequencing, which included the following panel of genes: ABCA1, ABCG1, ABCG5, ABCG8, ANGPTL3, APOA1, APOA2, APOA4, APOA5, APOB, APOC1, APOC2, APOC3, APOE, APOH, CETP, CH25H, CIDEC, CREB3L3, GPD1, GPIHBP1, LCAT, LDLR, LDLRAP1, LIPA, LIPC, LIPE, LIPG, LMF1, LPA, LPL, MTTP, MYLIP, NPC1, NPC1L1, NPC2, PCSK9, PLTP, PPP1R17, SAR1B, SCARB1, STAP1. Results: 24 (29.6%) patients had Lp(a) 30 mg/dl and were more likely to have a family history of CAD (70.8% vs 42.1%, p=0.05). In patients with a confirmed FH phenotype, there were no pathogenic variants associated with hereditary disorders of lipid metabolism. 4 patients with Lp(a) 30 mg/dl without a confirmed FH phenotype appeared to be carriers of pathogenic variants in the genes of lipid metabolism (LDLR p.Glu763Asp, ABCA1 p.Arg1128His, APOA5 p.His321Le), as well as of a not previously registered variant in the LIPE gene NM_005357.4:c. 2312TC. Conclusions: Lp(a) can be an appropriate marker for revealing pathogenic variants in the genes of the lipid metabolism system in patients without the clinical FH phenotype with an early CAD manifestation.

Abstract Background There is an increased concern that statins may have an unintended effect of elevated lipoprotein(a) [Lp(a)]. We conducted a large sample real-world study to test the association. Methods This retrospective cohort study was conducted using data from an integrated SuValue database, which includes 221 hospitals across China covering more than 200,000 of population with longitudinal follow-up to 10 years. Propensity score matching was applied to identify two comparable cohorts with statin users and non-statin users. Detailed follow-up information such as Lp(a) levels were extracted. The hazard ratio was calculated on Lp(a) changes based on the statin usage cohorts. Detailed subgroup and different characteristic cohorts’ analyses were also conducted. Results After baseline propensity score matching, a total of 42,166 patients were included in a 1:1 matched ratio between statin users and non-statin users. In the case of no difference in low density lipoprotein (LDL-C), Lp(a) was increased significantly with the use of statins (adjusted HR 1.47; 95% confidence interval [CI] 1.43–1.50). Lp(a) increase was observed in various subgroup analyses and different cohorts. The dose intensity of statin was positively associated with the evaluated Lp(a) level. Conclusion The use of statins was associated with an increased risk of Lp(a) elevation compared with non-statin use counterparts. The clinical relevance of these increases needs to be addressed in surrogate marker trials and/or large, cardiovascular outcomes trials.

OBJECTIVE: To evaluate gender difference in non-traditional cardiovascular risk factors among Saudi patients with angiographically defined coronary artery disease (CAD). METHODS: We recruited 144 (male=105, female=39) patients with CAD who underwent coronary angiography. Laboratory analysis of total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), lipoprotein(a) [Lp(a)], and high sensitivity C-reactive protein (hs-CRP) were performed along with echocardiographic evaluation. RESULTS: Systolic blood pressure (SBP) was significantly higher in females (138.65±18.67 vs 129.59±21.03 mmHg; p=0.0363). Although no significant difference was observed in TC (4.30±1.36 vs 4.67±1.07 mmol/L), however significantly higher levels of both HDL and LDL were seen in females (0.86±0.17 vs 0.70±0.23 mmol/L; p=0.0592 and 3.50±0.67 vs 2.72±1.13; p=0.0466 respectively). There were no significant differences in TG, Lp(a) and hs-CRP, however females had comparatively higher Lp(a) (30.43±28.89 vs 24.02±23.42 mg/dl) and hs-CRP (1.14±1.46 vs 0.95±1.25 mg/L). On angiography, greater extent of stenosis was observed in left anterior descending and right coronary arteries among males, while the left circumflex artery was affected more in the female patients without statistical significance (p=0.0797; 0.3890 and 0.5032 respectively). Gensini Score in males & females was 60.46±46.17 and 74.39±39.52 respectively (p=0.3013). Significantly narrower aortic root diameter (ARD) was observed among females (27.30±6.66 vs 29.73±3.40 mm; p=0.0293). CONCLUSION: Female patients have greater risk of cardiovascular diseases due to higher SBP and LDL levels which could lead to a greater Gensini score when compared to male patients. In addition, narrow ARD among females could also be a contributing factor to CAD.

Abstract Aim At present, the relationship between serum homocysteine (Hcy), fibrinogen (FIB), lipoprotein-a (LPa), and PAD is uncertain, and there has been no meta-analysis to establish the dose–response relationship between their exposure levels and PAD. Methods and results Relevant literature published in PubMed, Embase, and Web of Science was retrieved. The robust error meta-regression method was used to assess the linear and non-linear dose–response relationship between exposure level and PAD risk. A total of 68 articles, involving 565,209 participants, were included. Combined with continuous variables, the serum Hcy, FIB, and LPa levels of PAD patients were significantly higher than those of healthy individuals. The odds ratios (ORs) of PAD for individuals with high Hcy, FIB, and LPa levels compared with those with low levels were 1.47, 1.14, and 1.76, respectively. The study also showed that circulating Hcy, FIB, and LPa were significantly elevated in patients with PAD compared with controls. The level of Hcy and the risk of PAD presented a U-shaped distribution. The nonlinear dose–response model showed that each 1 μmol/L increase in serum Hcy increased the risk of PAD by 7%. Similarly, for each 10 mg/dL FIB and 10 mg/dL LPa increases, the risk of PAD increased by 3% and 6%, respectively. Conclusions This meta-analysis provided evidence that elevated Hcy, PIB, and LPa levels may increase the risk of PAD, and the risk of PAD increases with the increase in serum exposure within a certain range. By controlling Hcy level, the incidence of PAD may be reduced to control the PAD growing epidemic. Trial registration number: PROSPERO (CRD42021250501), https://www.crd.york.ac.uk/prospero/

Abstract Background Lipoprotein(a) [Lp(a)] is one of the residual risk factors for cardiovascular disease (CVD) in the setting of optimal low-density lipoprotein cholesterol (LDL-C). The association between Lp(a) and CVD is still in the exploratory phase, with few studies indicating a causal connection between Lp(a) and various CVD. Methods Lp(a) (n = 377,590) was a genome-wide association study (GWAS) based on European populations from Neale Lab. Large GWAS datasets for CVD, including aortic aneurysm(AA) (n = 209,366), atrial fibrillation(AF) (n = 1,030,836), coronary heart disease(CHD) (n = 361,194), secondary hypertension(HBP) (n = 164,147), heart failure(HF) (n = 208,178), ischemic stroke (IS) (n = 218,792), large artery atherosclerosis stroke(ISL) (n = 150, 765), small vessel stroke(ISS) (n = 198,048), lacunar stroke(LIS) (n = 225,419), and pulmonary embolism(PE) (n = 218,413) were also based on European populations. We performed separate univariate two-sample Mendelian randomization (MR) analysis for Lp(a) and CVD as described above. We evaluated this connection mainly using the random-effects inverse variance weighted technique(IVW1) with a 95% confidence interval (CI) for the odds ratio (OR). This was supplemented by MR-Egger, weighted median, maximum likelihood, penalized weighted median, and fixed-effects inverse variance weighted methods. MR-PRESSO offers another means of statistical detection. Results Our two-sample MR, which was predominately based on IVW1, revealed a causal relationship between Lp(a) and AA (OR = 1.005, 95%CI: 1.001–1.010, P = 0.009), CHD (OR = 1.003, 95%CI 1.001–1.004, P = 0.010), and ISL (OR = 1.003, 9 5%CI 1.002–1.004, P = 9.50E−11), in addition, there is no causal association with AF, HBP, HF, IS, ISS, LIS, or PE. Similar conclusions were reached by the MR-PRESSO method. Conclusion This MR study suggested a causal relationship between Lp(a) and CHD, AA, and ISL, but not associated with AF, HF, IS, LIS, ISS, HBP, or PE. Our work further verifies the association between Lp(a) and various CVD, resulting in improved Lp(a) management and a reduction in the prevalence of CVD.

Aim of the study: to assess the relationship between Lp(a) serum levels grading and carotid artery stenosis (CAS). The Duplex Registry database was used for this study. CAS was verified by duplex scanning in the presence of an atherosclerotic plaque (AP), stenosing the lumen of the carotid artery (CA) by 20 % or more. Patients who underwent a blood test for Lp(a) and the results were entered into the registry database were selected for this study. The immunoturbidimetric method was used to determine the serum level of Lp(a) (mg/dl). Data from 51 patients (66.6 % men) were included in the final analysis: median age 49.0 [46.0; 59], total cholesterol (TC) 5.93 [5.13; 6.56], Lp(a) 26.5 [14.2; 76.0]. Spearman rank correlation analysis showed the presence of significant relationships (p < 0.05) between Lp(a) and age (r = 0.3), gender (r = 0.3), the presence of AP in the right ICA (r = 0.5), HDL (r = 0.3). OR and 95 % CI were calculated to determine the effect of Lp(a) grades on the probability of CAS detection: Lp(a) < 30 mg/dl OR 0.36 [0.11; 1.14] p = 0.04; Lp(a) > 30 mg/dl OR 1.42 [0.44; 4.58] p = 0.27. The prevalence of CAS in the group with Lp(a) level < 30 mg/dl was 33.3 %, 30–50 mg/dl – 50 %, 50–100 mg/dl – 40 %, > 100 mg/dl – 37.5 %. The model of multiple regression analysis for Lp(a) with TC in relation to the right ICA stenosis predicting showed R = 0.51, F = 8.4, p = 0.0007. The statistics of 3M model of the logistic regression function for CAS predicting based on the Lp(a) and TC data showed: -2 • log(likelihood) = 57.16, Chi-square = 8.17 (cc = 2), p = 0.016. The present study confirmed the relationship between the Lp(a) level and the CAS detection and the presence of an additive effect of total cholesterol on this. The reference role of Lp(a) gradation at the level of 30 mg/dl was determined as significant in relation to predicting CAS detection.

The objective of our study was to examine the contribution of elevated Lp(a) to 10-year mortality in 140 CAD patients, depending on gender, baseline lipid levels, ApoA-I, ApoB, and the ApoA1, ApoE, and ApoB gene polymorphisms. Methods and Results: The study included 140 patients (75 men and 65 women) of the Uzbek population, hospitalized with diagnosis “CAD, unstable angina (IIB class, E. Braunwald et al., 1989)” (main group) in the period between January 2009 and February 2011. The endpoints at 10-year follow-up were death from cardiovascular causes (fatal myocardial infarction and sudden cardiac death). In the studied cohort of CAD patients, Lp(a) distribution was skewed to the right, the median was 16.9mg/dL, and the mean was 34.3mg/dL. At the same time, Lp(a) value greater than the 75th percentile was >41mg/dL. In this regard, we compared the baseline values in 2 groups of patients: Group 1 (Lp(a)41mg/dL). The 10-year cardiovascular mortality rate was higher significantly in Group 2 (RR =3.67; 95% CI: 1.67-8.11; P=0.0013). Cardiovascular mortality was significantly higher (P41mg/dL is a factor that increases 10-year mortality in CAD patients. Highlights • 10-year cardiovascular mortality was higher in CAD patients with Lp(a)>41mg/dL. • However, the increase in mortality due to high Lp(a) was statistically significant in men than in women. • The ApoA-I level was higher in women than in men. • Cardiovascular mortality was lower in patients with ApoA-I≥140mg/dL, most of whom were women.

Abstract Background Currently, remnant cholesterol (RC), lipoprotein(a) [Lp(a)], and inflammation are considered the principal residual cardiovascular risk (RCVR) factors. This study sought to evaluate the combined impact of RC, Lp(a), and inflammation on prognosis of statin-treated patients with chronic coronary syndrome (CCS), which has not been investigated. Methods A total of 6839 patients with CCS were consecutively enrolled. Baseline RC, Lp(a), and high-sensitivity C-reactive protein (hsCRP) concentrations were measured and their medians were used for categorizations. All patients were followed for the major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal myocardial infarction, and stroke. The individual and combined effects of RC, Lp(a), and hsCRP on MACEs were examined and stratification analysis according to low-density lipoprotein cholesterol (LDL-C) was performed. Results Over an average of 54.93 ± 18.59 months follow-up, 462 MACEs were recorded. Multivariate Cox analysis showed that elevated RC and Lp(a) levels were significantly associated with an increased risk of MACEs, while high hsCRP levels were related to a slightly but non-significantly increased MACEs risk. Moreover, when participants were subgrouped according to RC, Lp(a), and hsCRP levels together, only High RC-High Lp(a)-High hsCRP group had significantly higher risk of MACEs [hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.15–3.47] compared with the reference group (Low RC-Low Lp(a)-Low hsCRP), especially in patients with LDL-C

Background. Lipoprotein(a) (Lp(a)) is a genetic risk factor of atherosclerotic cardiovascular diseases (ASCVDs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is related to vascular inflammation and detected in atherosclerotic plaques. A temporary increase in the circulating concentration of PCSK9 and Lp(a) was shown in patients with myocardial infarction (MI). The aim of this study was to evaluate the role of the apo(a) phenotype and the Lp(a) concentration as well as its complex with PCSK9 in the development of cardiac events and MI in patients with a premature manifestation of coronary heart disease (CHD). Methods. In a prospective study with retrospective data collection, we included 116 patients with premature CHD who were followed for a median of 14 years. The medical history and information on cardiovascular events after an initial exam as well as data on the levels of lipids, Lp(a), PCSK9, PCSK9-Lp(a) complex, and apo(a) phenotype were obtained. Results. The patients were divided into two groups depending on the presence of a low- (LMW, n = 52) or high-molecular weight (HMW, n = 64) apo(a) phenotype. LMW apo(a) phenotype (odds ratio 2.3 (1.1 to 4.8), p = 0.03), but not elevated Lp(a) (1.9 (0.8–4.6), p = 0.13), was an independent predictor for the development of MI after adjustment for sex, age of CHD debut, initial lipids levels, and lipid-lowering treatment. The apo(a) phenotype also determined the relationship between Lp(a) and PCSK9 concentrations. The level of the PCSK9-Lp(a) complex was higher in LMW apo(a) patients. Conclusion. The LMW apo(a) phenotype is a risk factor for non-fatal MI in a long-term prospective follow-up of patients with premature CHD, and this link could be mediated via PCSK9.

The role of lipoprotein(a) [Lp(a)] in the development of atherosclerosis has been recently recognized, and the current recommendation is to measure Lp(a) once in a lifetime in all individuals, in order to identify those at risk for developing an acute coronary syndrome or recurrent events, even in the absence of other cardiovascular risk factors. We present the case of a middle-aged patient with recurrent cardiovascular events, in whom we identified high levels of Lp(a) as a possible explanation of the recurrent events.

Lipoprotein(a) [Lp(a)] is a lipid molecule with atherogenic, inflammatory, thrombotic, and antifibrinolytic effects, whose concentrations are predominantly genetically determined. The association between Lp(a) and cardiovascular diseases (CVDs) has been well-established in numerous studies, and the ability to measure Lp(a) levels is widely available in the community. As such, there has been increasing interest in Lp(a) as a therapeutic target for the prevention of CVD. The impact of the currently available lipid-modifying agents on Lp(a) is modest and heterogeneous, except for the monoclonal antibody proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), which demonstrated a significant reduction in Lp(a) levels. However, the absolute reduction in Lp(a) to significantly decrease CVD outcomes has not been definitely established, and the magnitude of the effect of PCSK9i seems insufficient to directly reduce the Lp(a)-related CVD risk. Therefore, emerging therapies are being developed that specifically aim to lower Lp(a) levels and the risk of CVD, including RNA interference (RNAi) agents, which have the capacity for temporary and reversible downregulation of gene expression. This review article aims to summarize the effects of Lp(a) on CVD and to evaluate the available evidence on established and emerging therapies targeting Lp(a) levels, focusing on the potential reduction of CVD risk attributable to Lp(a) concentrations.

The past few years have shown an ongoing interest in lipoprotein(a) (Lp(a)), a lipid molecule that has been proven to have atherogenic, thrombogenic, and inflammatory properties. Several lines of evidence, indeed, have demonstrated an increased risk of cardiovascular disease as well as calcific aortic valve stenosis in patients with elevated Lp(a) levels. Statins, the mainstay of lipid-lowering therapy, slightly increase Lp(a) levels, while most other lipid-modifying agents do not significantly alter Lp(a) concentrations, except for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The latter have been shown to reduce Lp(a) levels; however, the clinical significance of this effect has not been clearly elucidated. Of note, the pharmaceutical lowering of Lp(a) may be achieved with novel treatments specifically designed for this purpose (i.e., antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)). Large clinical trials with cardiovascular outcomes with these agents are ongoing, and their results are eagerly awaited. Furthermore, several non-lipid-modifying drugs of various classes may influence Lp(a) concentrations. We have searched MEDLINE, EMBASE, and CENTRAL databases up to 28 January 2023 and summarized the effects of established and emerging lipid-modifying drugs and other medications on Lp(a) levels. We also discuss the potent clinical implications of these alterations.

Introduction Lipoprotein(a) (Lp(a)) is recognized as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). The aim of this study was to estimate the distribution of Lp(a) levels in working age adults from the Russian population and to assess its association with ischemic heart disease (IHD), myocardial infarction (MI), stroke, diabetes mellitus (DM), and arterial hypertension (AH). Material and methods This substudy of the population-based study “Epidemiology of Cardiovascular Diseases and their Risk Factors in Some Regions of the Russian Federation” (ESSE-RF) included 8461 subjects aged 25–64 years (63.7% women) without lipid-lowering drugs. Atherosclerotic cardiovascular disease was self-reported. Lp(a), apolipoproteins AI and B, and lipid and glucose levels in blood serum were determined. Results The prevalence of Lp(a) ≥ 30 mg/dl was 20.5% and 23.0%, and prevalence of Lp(a) ≥ 50 mg/dl was 13.3% and 15.2%, in men and women, respectively. An association of Lp(a) with IHD, MI, and AH, but not with stroke and DM, was shown. A cut-off level of Lp(a) of 9 mg/dl was determined, above which there was increased frequency of MI (by 59.2%, p = 0.02), IHD (by 33.4%, p < 0.001), and AH (by 11.6%, p < 0.001). In the multivariate analysis only the association of Lp(a) with IHD (1.19 (1.01–1.41), p = 0.038) and MI (1.57 (1.06–2.38), p = 0.028) remained significant. Conclusions Lipoprotein(a) level ≥ 30 mg/dl was detected in every fifth adult aged 25–64 years. Increased risk of MI and IHD starts at an Lp(a) serum level above 9 mg/dl.

ABSTRACT Reports have shown that lipoprotein (Lp)(a) can serve as an indicator of atherosclerosis and cardiovascular diseases. Several cardiovascular disease risk factors including age, ethnicity and type 2 diabetes mellitus have been linked to Lp(a) metabolism. Given the structural similarity between Lp(a) and plasminogen, there may be a relationship between Lp(a) level and thrombosis and atherogenesis. In this review, we summarize the latest data about Lp(a) and related conditions on the PubMed database using the following keywords: “Lp(a) and diseases” and “Lp(a) and racial groups”. All available information was extracted and categorized according to the purpose of this study. In conclusion, evidence suggest that increased level of Lp(a) results in coronary artery disease and increases the risk of ischemic stroke. Lack of Lp(a) has no adverse effect on human health. Moreover, Lp(a) can be effective in wound healing as it degrades apolipoprotein(a) products which might have anti-tumor and anti-angiogenetic effects. Keywords: Lipoprotein(a), Atherosclerosis, Apo(a).

Aortic valve stenosis is the most common valvular heart disease in the Western world. Lipoprotein(a) (Lp(a)) is an independent risk factor of coronary heart disease (CHD) and calcific aortic valve stenosis (CAVS). The aim of this study was to assess the role of Lp(a) and its autoantibodies [autoAbs] in CAVS in patients with and without CHD. We included 250 patients (mean age 69 ± 3 years, males 42%) and divided them into three groups. There were two groups of patients with CAVS depending on the presence (group 1) or absence of CHD (group 2). The control group included the patients without CHD or CAVS. According to logistic regression analysis, levels of Lp(a), IgM autoAbs to oxidized Lp(a) (oxLp(a)), and age were independent predictors of CAVS. A concomitant increase in Lp(a) level (≥30 mg/dL) and a decrease in IgM autoAbs concentration (p < 0.01, and with CAVS and CHD with an OR of 17.3, p < 0.001. IgM autoantibodies to oxLp(a) are associated with calcific aortic valve stenosis regardless of Lp(a) concentration and other risk factors. Higher Lp(a) and lower IgM autoantibodies to oxLp(a) levels are associated with a much higher risk of calcific aortic valve stenosis.

Introduction: High values of lipoprotein(a), related to atherosclerosis progression, are often considered a marker of thrombosis. We assessed the lipoprotein(a) profile in a group of patients with high vascular risk and no cardiovascular events, established its correlation with other cardiovascular risk factors and inferred the results for patients with metabolic disorders and, at least, two risk factors. Material and Methods: This longitudinal observational study included 516 patients, who had at least two cardiovascular risk factors and regularly attended, for at least two years, the outpatient consultations at a clinic of metabolism and vascular risk for primary prevention. Sociodemographic, clinical and anthropometric parameters were obtained at the baseline visit. Hepatic morphology was assessed in 509 patients (98.6%) by ultrasonography. The 10-year vascular risk was estimated using Framingham risk score, atherosclerotic cardiovascular disease and systematic coronary risk evaluation tables. Results: Significant correlations were found between lipoprotein(a) levels and the addressed vascular risk factors, as well as between lipoprotein(a), and Framingham risk score, atherosclerotic cardiovascular disease and systematic coronary risk evaluation charts. Lipoprotein(a) values were also considerably higher in patients with steatosis. Discussion: Increased lipoprotein(a) values were directly associated with all markers of cardiovascular risk and with non-alcoholic hepatic steatosis. Conclusion: Due to its high availability and low cost, lipoprotein(a) should become part of the routine evaluation of patients at vascular risk.

Familial hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] level are the most common inherited disorders of lipid metabolism. This study evaluated the impact of high Lp(a) level on accuracy Dutch Lipid Clinic Network (DLCN) criteria of heterozygous FH diagnosis. A group of 206 individuals not receiving lipid-lowering medication with low-density lipoprotein cholesterol (LDL-C) >4.9 mmol/L was chosen from the Russian FH Registry. LDL-C corrected for Lp(a)-cholesterol was calculated as LDL-C − 0.3 × Lp(a). DLCN criteria were applied before and after adjusting LDL-C concentration. Of the 206 patients with potential FH, a total of 34 subjects (17%) were reclassified to less severe FH diagnosis, 13 subjects of them (6%) were reclassified to “unlike” FH. In accordance with Receiver Operating Characteristic curve, Lp(a) level ≥40 mg/dL was associated with FH re-diagnosing with sensitivity of 63% and specificity of 78% (area under curve = 0.7, 95% CI 0.7–0.8, p < 0.001). The reclassification was mainly observed in FH patients with Lp(a) level above 40 mg/dL, i.e., 33 (51%) with reclassified DLCN criteria points and 22 (34%) with reclassified diagnosis, compared with 21 (15%) and 15 (11%), respectively, in patients with Lp(a) level less than 40 mg/dL. Thus, LDL-C corrected for Lp(a)-cholesterol should be considered in all FH patients with Lp(a) level above 40 mg/dL for recalculating points in accordance with DLCN criteria.

Aim. Lipoprotein(a) [Lp(a)] is an independent risk factor of coronary heart disease (CHD) and myocardial infarction. Data about the role of Lp(a) in the development of peripheral artery disease (PAD) is controversial and uncertain. The aim of the study was to evaluate the association between Lp(a), apolipoprotein(a) [apo(a)] phenotypes and PAD. Materials and methods. The study included 998 patients (707 male and 291 female, average age 60±12). The patients were divided into 4 groups depending on the presence or absence PAD and CHD: group I (n=188, PAD+CHD+), group II (n=78, PAD+CHD-), group III (n=407, PAD-CHD+), group IV (n=325, PAD-CHD-). Results. The level of Lp(a) was significantly higher in groups I, II, III in comparison with patients of control group (group IV): 34 [15; 80], 30 [10; 49], 22 [8; 60] mg/dl vs. 15 [6; 35] mg/dl respectively, p

Serum lipids abnormalities are widespread among patients with chronic hepatitis C (CHC), but the impact of concomitant hepatic steatosis [steatosis, nonalcoholic steatosis (NAS)], as well as distinctions between it and nonalcoholic fatty liver disease (NAFLD) are not well established yet. The aim of the study was to assess and compare the serum lipids in patients with genotype 1 CHC with and without steatosis, those with NAFLD, and healthy controls (HC). A total of 1010 subjects were included in this study: 366 CHC genotype 1 patients with steatosis (n = 227) and without steatosis (n = 139), 403 NAFLD patients, and 241 HC without fatty liver or other disease, matched for age and gender. Serum lipids, body mass index (BMI), components of metabolic syndrome (MS), and serum insulin levels were evaluated. In addition serum lipoprotein (a) [Lp(a)] levels were studied in 112 CHC and 80 NAFLD patients. The mean levels of total cholesterol, LDL-cholesterol and triglycerides (Tg) were higher and the mean levels of HDL-cholesterol were lower in all patients with steatosis (CHC and NAFLD) than in CHC cases without steatosis (p < 0.05 and p = 0.001, resp.). Higher prevalence and severity of lipid abnormalities, including Lp(a), were observed in patients with NAFLD than in those with CHC (p < 0.001). No difference was found between CHC patients without steatosis and HC. Higher prevalence and grade of glucose metabolic abnormalities were also observed in patients with NAFLD and CHC with steatosis than in cases without steatosis (p < 0.05 and p = 0.001, resp.). Lipid and glucose metabolic abnormalities in patients with CHC were dependent on steatosis. CHC with steatosis and NAFLD were associated with insulin resistant type dyslipidemia, with total cholesterol and LDL-cholesterol being generally lower in CHC.

Introduction: Data on relationship between lipoprotein(a) [Lp(a)] and non-ischemic heart dysfunction are limited. This study is aimed to assess the association between Lp(a) and left ventricular systolic dysfunction in a Chinese population of patients with hypertension and without coronary artery disease (CAD). Material and methods: This cross-sectional study included 1611 patients with hypertension and without CAD in China. The factors associated with left ventricular ejection fraction (LVEF) were evaluated using univariate and multivariate analysis. Results : A higher percentage of hypertensive patients with LVEF