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Association between lipoprotein(a) concencentration and isoform size (Reproduced from Reference [21]). Apo(a) = apolipoprotein (a), Lp(a) = lipoprotein (a), LMW = low molecular weight, HMW = high molecular weight, KIV = kringle number repeats.
Source publication
There is now significant evidence to support an independent causal role for lipoprotein(a) (Lp(a)) as a risk factor for atherosclerotic cardiovascular disease. Plasma Lp(a) concentrations are predominantly determined by genetic factors. However, research into Lp(a) has been hampered by incomplete understanding of its metabolism and proatherogeneic...
Citations
... The National Lipid Association pooled data from large prospective, population-based studies and found that when compared to patients with Lp(a) < 5 mg/dL, those with Lp(a) Lp(a) ≥ 120 mg/dL were at a 5-fold risk of coronary artery stenosis, 3-to 4-fold risk of myocardial infarction, 1.7-fold risk of carotid stenosis, 1.6-fold risk of ischemic stroke, 3-fold risk of aortic stenosis, and 1.6-fold risk of femoral artery stenosis, suggesting CAD likely has a greater association with Lp(a) than PAD and CeVD [4]. Lp(a) levels are 90% genetically determined and not appreciably affected by diet or exercise; therefore, serum levels typically remain stable in individuals over their lifetime [5,6]. Although the consequences of elevated Lp(a) levels are well described, testing remains sparse. ...
Lipoprotein(a) is a low-density-lipoprotein-like particle that consists of apolipoprotein(a) bound to apolipoprotein(b). It has emerged as an established causal risk factor for atherosclerotic cardiovascular disease, stroke, and aortic valve stenosis through multifactorial pathogenic mechanisms that include inflammation, atherogenesis, and thrombosis. Despite an estimated 20% of the global population having elevated lipoprotein(a) levels, testing remains underutilized due to poor awareness and a historical lack of effective and safe therapies. Although lipoprotein(a) has a strong association with coronary artery disease and cerebrovascular disease, its relationship with peripheral artery disease is less well established. In this article, we review the epidemiology, biology, and pathogenesis of lipoprotein(a) as it relates to peripheral artery disease. We also discuss emerging treatment options to help mitigate major adverse cardiac and limb events in this population.
... Particles with a higher number of KIV-2 repeats are larger and heavier, an estimated mass difference of 19% has been reported between an Lp(a) particle with 6 KIV-2 repeats in apo(a) compared to Lp(a) with 35 KIV-2 repeats, and therefore the measurement of Lp(a) concentration may be partly artefactual when using assays that are not isoform independent. 28 These measurement errors primarily affect quantifications with extreme results, underestimating the concentrations of samples from individuals with small Lp(a) isoforms (associated with higher Lp(a) levels) and vice versa. 29 This is particularly important because thus the risk of patients with small Lp(a) isoforms and vice versa would be underestimated. ...
The irruption of lipoprotein(a) (Lp(a)) in the study of cardiovascular risk factors is perhaps, together with the discovery and use of proprotein convertase subtilisin/kexin type 9 (PCSK9i) inhibitor drugs, the greatest novelty in the field for decades. Lp(a) concentration (especially very high levels) has an undeniable association with certain cardiovascular complications, such as atherosclerotic vascular disease (AVD) and aortic stenosis. However, there are several current limitations to both establishing epidemiological associations and specific pharmacological treatment. Firstly, the measurement of Lp(a) is highly dependent on the test used, mainly because of the characteristics of the molecule. Secondly, Lp(a) concentration is more than 80% genetically determined, so that, unlike other cardiovascular risk factors, it cannot be regulated by lifestyle changes. Finally, although there are many promising clinical trials with specific drugs to reduce Lp(a), currently only PCSK9i (limited for use because of its cost) significantly reduces Lp(a).
However, and in line with other scientific societies, the SEA considers that, with the aim of increasing knowledge about the contribution of Lp(a) to cardiovascular risk, it is relevant to produce a document containing the current status of the subject, recommendations for the control of global cardiovascular risk in people with elevated Lp(a) and recommendations on the therapeutic approach to patients with elevated Lp(a).
... We removed those SNPs associated with potential confounding at a Bonferroni corrected level (P < 0.05/number of SNPs), including smoking, drinking, Townsend deprivation index, physical activity, body mass index, Hemoglobin A1c, Diastolic Blood Pressure, and Systolic Blood Pressure. As a result, we used 65 SNPs as instrumental variables for LDL-C, 69 SNPs for HDL-C, 43 Tables S2-S7). For each lipid trait, we generated a weighted genetic risk score (GRS) by using the allelic effect of the SNPs as reported in previous public GWAS. ...
... The exact mechanism behind these associations is unclear, but it has been proposed that Lp(a) mediates clinical events primarily through three mechanisms. First, Lp(a) contains a moiety similar to low-density lipoprotein, with one ApoB molecule that can accelerate atherosclerosis (43). Second, the high homology of its apolipoprotein(a) component to the fibrinolytic proenzyme plasminogen suggests a potential antifibrinolytic role for Lp(a), which can interfere with the binding of plasminogen to fibrin and ultimately contribute to the formation of atherogenic plaques (44). ...
Dyslipidemia has long been implicated in elevating mortality risk; yet, the precise associations between lipid traits and mortality remained undisclosed. Our study aimed to explore the causal effects of lipid traits on both all-cause and cause-specific mortality. One-sample Mendelian randomization (MR) with linear and nonlinear assumptions was conducted in a cohort of 407,951 European participants from the UK Biobank. Six lipid traits, consisting of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were included to investigate the causal associations with mortality. Two-sample MR was performed to replicate the association between each lipid trait and all-cause mortality. Univariable MR results showed that genetically predicted higher ApoA1 was significantly associated with a decreased all-cause mortality risk (HR[95% CI]:0.93 [0.89–0.97], P value = 0.001), which was validated by the two-sample MR analysis. Higher lipoprotein(a) was associated with an increased risk of all-cause mortality (1.03 [1.01–1.04], P value = 0.002). Multivariable MR confirmed the direct causal effects of ApoA1 and lipoprotein(a) on all-cause mortality. Meanwhile, nonlinear MR found no evidence for nonlinearity between lipids and all-cause mortality. Our examination into cause-specific mortality revealed a suggestive inverse association between ApoA1 and cancer mortality, a significant positive association between lipoprotein(a) and cardiovascular disease mortality, and a suggestive positive association between lipoprotein(a) and digestive disease mortality. High LDL-C was associated with an increased risk of cardiovascular disease mortality but a decreased risk of neurodegenerative disease mortality. The findings suggest that implementing interventions to raise ApoA1 and decrease lipoprotein(a) levels may improve overall health outcomes and mitigate cancer and digestive disease mortality.
... Lipoprotein(a) [Lp(a)] is one of the atherogenic particles included in the non-HDL fraction of circulating lipoproteins. Lp(a) is characterized by having in its structure an LDL particle attached to an apoprotein(a) that presents heterogeneity in size [1][2][3]. Both observational and genetic studies have widely described the association between elevated levels of Lp(a) and the development of atherosclerotic cardiovascular disease (CVD) and aortic valve stenosis [2,[4][5][6]. ...
... Both observational and genetic studies have widely described the association between elevated levels of Lp(a) and the development of atherosclerotic cardiovascular disease (CVD) and aortic valve stenosis [2,[4][5][6]. It is known that plasma Lp(a) values are 90 % genetically determined and their levels are not associated with traditional cardiovascular risk factors [1]. Although the pathophysiological mechanisms that lead to cardiovascular damage have not been fully described so far, it has been proposed that Lp(a) does not only actively promote cholesterol accumulation in the intima of vessels and aortic valves inducing a pro-oxidative and inflammatory context, but it also participates in processes of inhibition of plasma fibrinolysis [2,7]. ...
... A review by Ward N. et al. in 2019 [1] showed different types of discrepancies in Lp(a) assessment and management recommendations in current clinical practice guidelines. Population subgroups for which the evaluation of this risk marker is recommended is not universally defined. ...
Background
Elevated Lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular disease (CVD) risk. There are discrepancies regarding its epidemiology due to great variability in different populations. This study aimed to evaluate the prevalence of elevated Lp(a) in people with moderate CVD risk and increased LDL-c and to determine the association between family history of premature CVD and elevated Lp(a).
Methods
Random subjects from the CESCAS population-based study of people with moderate CVD risk (Framingham score 10–20 %) and LDL-c ≥ 130 mg/dL, were selected to evaluate Lp(a) by immunoturbidimetry independent of the Isoforms variability. The association between family history of premature CVD and elevated Lp(a) was evaluated using multivariate logistic regression models. Elevated Lp(a) was defined as Lp(a) ≥ 125 nmol/L.
Results
Lp(a) was evaluated in 484 samples; men = 39.5 %, median age = 57 years (Q1-Q3: 50–63), mean CVD risk = 14.4 % (SE: 0.2), family history of premature CVD = 11.2 %, Lp(a) median of 21 nmol/L (Q1-Q3: 9–42 nmol/L), high Lp(a) = 6.1 % (95 % CI = 3.8–9.6). Association between family history of premature CVD and elevated Lp(a) in total population: OR 1.31 (95 % CI = 0.4, 4.2) p = 0.642; in subgroup of people with LDL-c ≥ 160 mg%, OR 4.24 (95 % CI = 1.2, 15.1) p = 0.026.
Conclusions
In general population with moderate CVD risk and elevated LDL-c from the Southern Cone of Latin America, less than one over ten people had elevated Lp(a). Family history of premature CVD was significantly associated with the presence of elevated Lp(a) in people with LDL-c ≥ 160 mg/dL.
... It has been proposed that the physiological role of Lp(a) may be to promote wound healing. Its normal concentration does not exceed 30 mg/dL (75 nmol/L), in some people no Lp(a) can be detected [3]. It is interesting that Lp(a) is only found in human beings, in old world monkeys, and hedgehogs. ...
... This particle is similar to plasminogen with a size ranging from 300 to 700 kDa. [3]. ...
... Lp(a) stimulates the secretion of PAI-1. However, high Lp(a) concentrations were not associated with the risk of venous thrombosis or venous thromboembolism in clinical trials [3]. ...
Lipoprotein(a) (Lp(a)) is a low density lipoprotein particle that is associated with poor cardiovascular prognosis due to pro-atherogenic, pro-thrombotic, pro-inflammatory and pro-oxidative properties. Traditional lipid-lowering therapy does not provide a sufficient Lp(a) reduction. For PCSK9 inhibitors a small reduction of Lp(a) levels could be shown, which was associated with a reduction in cardiovascular events, independently of the effect on LDL cholesterol. Another option is inclisiran, for which no outcome data are available yet. Lipoprotein apheresis acutely and in the long run decreases Lp(a) levels and effectively improves cardiovascular prognosis in high-risk patients who cannot be satisfactorily treated with drugs. New drugs inhibiting the synthesis of apolipoprotein(a) (an antisense oligonucleotide (Pelacarsen) and two siRNA drugs) are studied. Unlike LDL-cholesterol, for Lp(a) no target value has been defined up to now. This overview presents data of modern capabilities of cardiovascular risk reduction by lowering Lp(a) level.
... Lp(a) resembles LDL, with an LDL lipid core and apoB, but contains a unique highly glycosylated apolipoprotein, apo(a), linked to apoB via a single disulfide bond (Hoover-Plow and Huang, 2013;Jawi et al., 2020;Leibundgut et al., 2013). apo(a) contains variable amounts of Kringle structures and the plasminogen-like Kringle type IV (KIV) repeats endowed with multiple lysine binding sites (LBS) responsible in part for the physiological and pathological properties of this lipoprotein (Jawi et al., 2020;Leibundgut et al., 2013;Ward et al., 2019). The presence of LBS renders Lp(a) vulnerable to covalent modification by MDA and HNE adducts in an environment of chronic inflammation and oxidative stress, which changes the conformation and functions of the complex rendering it immunogenic and capable of activating PRRs and increasing levels of localised and systemic inflammation (Bergmark et al., 2008;Hiraya et al., 2019;Wadhwa et al., 2019). ...
Chronic systemic inflammation is associated with an increased risk of cardiovascular disease in an environment of low low-density lipoprotein (LDL) and low total cholesterol and with the pathophysiology of neuroprogressive disorders. The causes and consequences of this lipid paradox are explored. Circulating activated neutrophils can release inflammatory molecules such as myeloperoxidase and the pro-inflammatory cytokines interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha. Since activated neutrophils are associated with atherosclerosis and cardiovascular disease and with major depressive disorder, bipolar disorder and schizophrenia, it seems reasonable to hypothesise that the inflammatory molecules released by them may act as mediators of the link between systemic inflammation and the development of atherosclerosis in neuroprogressive disorders. This hypothesis is tested by considering the association at a molecular level of systemic inflammation with increased LDL oxidation; increased small dense LDL levels; increased lipoprotein (a) concentration; secretory phospholipase A2 activation; cytosolic phospholipase A2 activation; increased platelet activation; decreased apolipoprotein A1 levels and function; decreased paroxonase-1 activity; hyperhomocysteinaemia; and metabolic endotoxaemia. These molecular mechanisms suggest potential therapeutic targets.
... Существует обратная корреляция между концентрацией Лп (а) и размером изоформы апо (а). Высокое содержание Лп (a) определяет наличие низкомолекулярных изоформ и наоборот [6]. Такая вариабельность размеров является уникальным явлением в отличие от других липопротеинов, обычно имеющих постоянные молекулярные массы. ...
... Исходя из этого, можно предположить, что на популяционном уровне наибольшему риску будут подвержены люди с экстремально высокими уровнями Лп (а). Следовательно, методы лечения, снижающие Лп (а), будут более эффективными только при крайне высоких концентрациях, в то время как статины могут влиять на риск при любом исходном уровне ЛПНП [6,38,39]. ...
... Несмотря на то, что в большинстве проводимых исследований о содержании Лп (а) сообщается в виде массовой концентрации (мг/дл), в настоящее время рекомендуется отражать значения Лп (а) в молярных концентрациях (ммоль/л), так как в данном случае определяется общее количество частиц апо (а), независящее от переменной молекулярной массы Лп (a). При этом не существует стандартизированного метода для преобразования измерений Лп (а) из мг/дл в ммоль/л [6,40]. Говоря об аналитических вопросах, необходимо отметить, что формула Фридвальда, обычно используемая для расчета содержания холестерина ЛПНП, не учитывает холестерин, содержащийся в Лп (a). ...
Lipoprotein(a) [Lp(a)] is a subclass of lipoproteins consisting of a cholesterol-rich low-density lipoprotein (LDL) particle with a single apolipoprotein B100 molecule covalently bound (via a disulfide bridge) to a unique hydrophilic high-glycosylated protein called apolipoprotein a [apo(a)]. To date, there is sufficient evidence to consider an increase Lp(a) level as a causal and independent risk factor for cardiovascular disease and calcifying aortic valve stenosis. Plasma concentration of Lp(a) can vary in a wide range, which is mainly determined by genetic factors. Up to 30 % of the world's population has an elevated Lp(a) level, but this category of lipid disorders has not been currently receiving adequate attention. Determining the Lp(a) plasma concentrations is not included in the standard lipid profile, so a significant number of individuals with hyperlipoproteinemia(a) who could potentially benefit from treatment remain undiagnosed. Certain significant obstacles are still associated with the lack of standardized assay for measuring Lp(a) concentrations and a consensus on its optimal levels in blood plasma. Although some limited but statistically significant data suggest a possible benefit of lipoprotein(a) lowering on cardiovascular outcomes, no specific recommendations were made for the management of that dyslipidemia in the latest guidelines. Plasma Lp(a) levels reflect a balance of Lp(a) synthesis, which occurs in the liver, and catabolism, which is thought to involve the kidney. Lp(a) concentration begins already to increase in the earliest stages of chronic kidney disease, and patients with nephrotic syndrome have a four-fold elevated Lp(a) in comparison to healthy individuals. However, it remains unclear if elevated Lp(a) levels affect cardiovascular risk in patients with kidney diseases. This article summarizes the main data regarding the relationship between Lp(a) content, impaired renal function, and an increased risk of adverse cardiovascular events. Keywords: lipoprotein(a), kidney diseases, cardiovascular risk.
... Although testing for Lp(a) was not recommended in 2011, recent guidelines by multiple professional societies and reviews have highlighted the role of Lp(a) as an independent risk factor for premature ASCVD, and several addressed screening of Lp(a) in youth 2,4 and adults. 5 The gene for Lp(a) is inherited in an autosomal dominant fashion with high fidelity. Lp(a) levels double over the first year of life, and the apo(a) gene product is fully expressed by the first or second year of life and remains stable throughout the lifespan, a pattern strikingly different from that of other lipoproteins. ...
Risk factor screening of all youth, including those with high-risk medical conditions such as diabetes mellitus, is important to reduce premature morbidity and mortality attributable to atherosclerotic cardiovascular disease. In those found to have significant hypercholesterolemia and/or elevated levels of lipoprotein (a), reverse cascade screening (child to parent) is recommended. This case demonstrates the benefits of targeted lipid testing. Early detection may provide additional motivation for families to adopt healthier lifestyles and reduce future atherosclerotic cardiovascular disease events in the child, siblings, and parents.
Elevated lipoprotein(a) is a genetically transmitted codominant trait that is an independent risk driver for cardiovascular disease. Lipoprotein(a) concentration is heavily influenced by genetic factors, including LPA kringle IV‐2 domain size, single‐nucleotide polymorphisms, and interleukin‐1 genotypes. Apolipoprotein(a) is encoded by the LPA gene and contains 10 subtypes with a variable number of copies of kringle ‐2, resulting in >40 different apolipoprotein(a) isoform sizes. Genetic loci beyond LPA , such as APOE and APOH , have been shown to impact lipoprotein(a) levels. Lipoprotein(a) concentrations are generally 5% to 10% higher in women than men, and there is up to a 3‐fold difference in median lipoprotein(a) concentrations between racial and ethnic populations. Nongenetic factors, including menopause, diet, and renal function, may also impact lipoprotein(a) concentration. Lipoprotein(a) levels are also influenced by inflammation since the LPA promoter contains an interleukin‐6 response element; interleukin‐6 released during the inflammatory response results in transient increases in plasma lipoprotein(a) levels. Screening can identify elevated lipoprotein(a) levels and facilitate intensive risk factor management. Several investigational, RNA‐targeted agents have shown promising lipoprotein(a)‐lowering effects in clinical studies, and large‐scale lipoprotein(a) testing will be fundamental to identifying eligible patients should these agents become available. Lipoprotein(a) testing requires routine, nonfasting blood draws, making it convenient for patients. Herein, we discuss the genetic determinants of lipoprotein(a) levels, explore the pathophysiological mechanisms underlying the association between lipoprotein(a) and cardiovascular disease, and provide practical guidance for lipoprotein(a) testing.
The irruption of lipoprotein(a) (Lp(a)) in the study of cardiovascular risk factors is perhaps, together with the discovery and use of proprotein convertase subtilisin/kexin type 9 (iPCSK9) inhibitor drugs, the greatest novelty in the field for decades. Lp(a) concentration (especially very high levels) has an undeniable association with certain cardiovascular complications, such as atherosclerotic vascular disease (AVD) and aortic stenosis. However, there are several current limitations to both establishing epidemiological associations and specific pharmacological treatment. Firstly, the measurement of Lp(a) is highly dependent on the test used, mainly because of the characteristics of the molecule. Secondly, Lp(a) concentration is more than 80% genetically determined, so that, unlike other cardiovascular risk factors, it cannot be regulated by lifestyle changes. Finally, although there are many promising clinical trials with specific drugs to reduce Lp(a), currently only iPCSK9 (limited for use because of its cost) significantly reduces Lp(a).
However, and in line with other scientific societies, the SEA considers that, with the aim of increasing knowledge about the contribution of Lp(a) to cardiovascular risk, it is relevant to produce a document containing the current status of the subject, recommendations for the control of global cardiovascular risk in people with elevated Lp(a) and recommendations on the therapeutic approach to patients with elevated Lp(a).
