Lipoprotein(a) [Lp(a)] structure. Lp(a) is composed of two parts: one part is low-density lipoprotein (LDL)-like particles with apolipoprotein B100 (apo-B100), and the other part is apolipoprotein a [apo(a)] covalently bound by disulfide bonds. Apo(a) contains 10 types of kringle IV (KIV) subtypes; one copy of both KIV1 and KIV3-10, and variable KIV2 repetition. In addition, apo(a) is composed of kringle V (KV) and an inactive protease-like domain (P). Created with BioRender.com.

Lipoprotein(a) [Lp(a)] structure. Lp(a) is composed of two parts: one part is low-density lipoprotein (LDL)-like particles with apolipoprotein B100 (apo-B100), and the other part is apolipoprotein a [apo(a)] covalently bound by disulfide bonds. Apo(a) contains 10 types of kringle IV (KIV) subtypes; one copy of both KIV1 and KIV3-10, and variable KIV2 repetition. In addition, apo(a) is composed of kringle V (KV) and an inactive protease-like domain (P). Created with BioRender.com.

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In recent years, epidemiological studies, genome-wide association studies, and Mendelian randomization studies have shown a strong association between increased levels of lipoproteins and increased risks of coronary heart disease and cardiovascular disease (CVD). Although lipoprotein(a) [Lp(a)] was an independent risk factor for ASCVD, the latest i...

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... is composed of two parts: a low-density lipoprotein (LDL)-like particle with apolipoprotein B100 (apo-B100), which is shared with apolipoprotein(a) [apo(a)] through disulfide binding (Fig. 1). [13][14][15][16] The existence of apo(a) determines the unique function of Lp(a). Apo(a) is composed of repeating kringle IV (KIV) and a protease-like domain. 17 According to the amino acid sequence, the KIV domain in apo(a) can be divided into 10 types (KIV1 to KIV10). Only KIV2 is repeated in the apo(a) sequence and the number of ...

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... Структурная схожесть апо(а) с плазминогеном также позволяет Лп(а) конкурировать с ним за места связывания на фибрине и блокировать плазминогеновые рецепторы на тромбоцитах [22], препятствуя действию тканевого активатора плазминогена (ТАП) и ингибируя его, что приводит к торможению работы системы фибринолиза [23] и опосредует тромботические осложнения, особенно у пациентов в группе риска. Лп(а) также нарушает гомеостаз систем гемостаза и фибринолиза, из-за особенностей строения Лп(а) воспринимается регуляторными системами как плазминоген, и по механизму обратной связи снижается синтез самого плазминогена [6]. ...
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Lipoprotein (а) is able to initiate mechanisms of inflammation and create an atherogenic and thrombophilic condition due to its structural features. It is important to acknowledge that there are currently no standardized protocols for the regular monitoring of lipoprotein (а) levels in clinical settings, despite its relevance in assessing cardiovascular risk among older patients. Even in the absence of abnormal lipid profiles, there may still be thickening of the arterial walls and the formation of atherosclerotic plaque. The extent of atherogenicity, or plaque development, is directly linked to plasma levels of lipoprotein (а), which have a genetic basis. This paper aims to review the role of lipoprotein (а) in low-grade inflammation and its pathogenic mechanisms in atherosclerosis, particularly in relation to elevated levels of this lipoprotein. The study will critically analyze the available literature on this topic to understand the potential role of lipoprotein (а) as a risk factor for atherosclerosis.
... As a result of plaque formation and rupture, individuals with elevated serum concentrations may experience myocardial infarction and ischemic stroke. Turbulent blood flow and calcification can lead to atherosclerotic stenosis and aortic valve stenosis [163,206,207]; SMC smooth muscle cell, EC endothelial cell, Lp(a) lipoprotein(a), Apo(a) apolipoprotein(a), ApoB-100 apolipoprotein B-100, OxPL oxidized phospholipids. Created with BioRender.com ...
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Numerous genetic and epidemiologic studies have demonstrated an association between elevated levels of lipoprotein(a) (Lp[a]) and cardiovascular disease. As a result, lowering Lp(a) levels is widely recognized as a promising strategy for reducing the risk of new-onset coronary heart disease, stroke, and heart failure. Lp(a) consists of a low-density lipoprotein-like particle with covalently linked apolipoprotein A (apo[a]) and apolipoprotein B-100, which explains its pro-thrombotic, pro-inflammatory, and pro-atherogenic properties. Lp(a) serum concentrations are genetically determined by the apo(a) isoform, with shorter isoforms having a higher rate of particle synthesis. To date, there are no approved pharmacological therapies that effectively reduce Lp(a) levels. Promising treatment approaches targeting apo(a) expression include RNA-based drugs such as pelacarsen, olpasiran, SLN360, and lepodisiran, which are currently in clinical trials. In this comprehensive review, we provide a detailed overview of RNA-based therapeutic approaches and discuss the recent advances and challenges of RNA therapeutics specifically designed to reduce Lp(a) levels and thus the risk of cardiovascular disease.
... The choice of a cutoff level at 30 mg/dl requires some explanation. In spite of the ESC/EAS recommendation of a cutoff value of 50 mg/dl, the literature has not unanimously identified such an Lp(a) value as critical for the increase in cardiovascular risk (53)(54)(55)(56)(57). Indeed, we also assessed the cutoff value of 50 mg/ dl (data not reported) but the results were consistent with those obtained with the lower cut off at 30 mg/dl and, moreover, included 31 more subjects and 5 events (3CVD, 1 TIA and 1 Stroke) in the HLp(a) patients, which increased the sensitivity of the comparison. ...
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Background and aims Epidemiology of atherosclerotic cardiovascular disease might be different in patients with polygenic hypercholesterolemia plus high levels (≥30 mg/dl) of Lp(a) (H-Lpa) than in those with polygenic hypercholesterolemia alone (H-LDL). We compared the incidence of peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CVD) in patients with H-Lpa and in those with H-LDL. Methods Retrospective analysis of demographics, risk factors, vascular events, therapy, and lipid profile in outpatient clinical data. Inclusion criteria was adult age, diagnosis of polygenic hypercholesterolemia, and both indication and availability for Lp(a) measurement. Results Medical records of 258 patients with H-Lpa and 290 H-LDL were reviewed for occurrence of vascular events. The median duration of follow-up was 10 years (IQR 3–16). In spite of a similar reduction of LDL cholesterol, vascular events occurred more frequently, and approximately 7 years earlier (P = 0.024) in patients with H-Lpa than in H-LDL (HR 1.96 1.21–3.17, P = 0.006). The difference was around 10 years for acute events (TIA, Stroke, acute coronary events) and one year for chronic ones (P = 0.023 and 0.525, respectively). Occurrence of acute CAD was higher in H-Lpa men (HR 3.1, 95% CI 1.2–7.9, P = 0.007) while, among women, PAD was observed exclusively in H-Lpa subjects with smoking habits (P = 0.009). Conclusions Patients with high Lp(a) levels suffer from a larger and earlier burden of the disease compared to those with polygenic hypercholesterolemia alone. These patients are at higher risk of CAD if they are men, and of PAD if they are women.
... Lp(a), which was identified several decades ago, has emerged as a potent risk factor for cardiovascular disease [3]. Lp(a) is a unique and complex plasma lipoprotein comprising an LDL-like particle covalently bound to apolipoprotein(a), a distinct protein bearing high homology to plasminogen, which plays an integral role in fibrinolysis. ...
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Background: This research delves into the association between altered lipid profiles and hypertensive disorders of pregnancy (HDP), shedding light on cardiovascular implications in maternal health. Methods: A cohort of 83 pregnant women was studied, with 48.19% diagnosed with HDP. This investigation primarily focused on Apolipoprotein B (ApoB) and Lipoprotein(a) (Lp(a)) as indicators of cardiovascular health. A comparative examination was conducted to determine discrepancies in the ApoB and Lp(a) levels between standard pregnancies and those presenting with HDP. Results: Significant elevations in ApoB (p value = 0.0486) and Lp(a) (p value < 0.0001) levels were observed in pregnant women with HDP compared to their counterparts with typical pregnancies. The pronounced link between heightened ApoB and Lp(a) concentrations and HDP persisted, even considering pregnancy’s distinct physiological conditions. Conclusions: Our research accentuates the crucial role of early detection and specialized handling of cardiovascular risks in expectant mothers, especially those predisposed to HDP. The study indicates ApoB and Lp(a)’s potential as reliable markers for gauging cardiovascular threats during gestation. Furthermore, our findings suggest an integrative care approach and guidance for pregnant women, aspiring to enhance cardiovascular health in the postpartum phase.
... High Lp(a) concentrations have been consistently linked to an increased risk of ischemic CVD, aortic valve stenosis, and heart failure. Both the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC) guidelines have suggested a threshold of 50 mg/dL of Lp(a) to mitigate an increased risk of CVD; however, some experts believe that the risk of CVD may already increase when Lp(a) plasma levels exceed 30 mg/dL [70]. The 2019 ESC/EAS guidelines recommend that individuals undergo at least one Lp(a) plasma level test in their lifetime. ...
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Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1–10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25–30%. Mipomersen decreases Lp(a) levels by 25–40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.
... In this study, no obvious difference in AEs was found between the 2 groups. Although Lp(a) is an independent risk factor for ASCVD, it is difficult to attribute the clinical benefit and AEs to Lp(a) reduction, and currently no drugs can selectively reduce Lp(a), including statins [65]. Approximately 30-50% of HeFH patients have elevated Lp(a) levels, and the cumulative burden of high Lp(a) is a strong driver of ASCVD for them [9]. ...
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Introduction: Familial hypercholesterolaemia (FH) is a common hereditary genetic disorder, characterized by elevated circulating low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] concentrations, leading to atherosclerotic cardiovascular disease (ASCVD). Two types of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors- alirocumab and evolocumab- are efficient drugs in the treatment of FH, which can effectively reduce Lp(a) levels. Material and methods: Embase, MEDLINE, and PubMed up to November 2022 were searched for randomized clinical trials (RCTs) evaluating the effect of alirocumab/evolocumab and placebo treatment on plasma Lp(a) levels in FH. Statistics were analysed by Review Manager (RevMan 5.3) and Stata 15.1. Results: Eleven RCTs involved a total of 2408 participants. Alirocumab/evolocumab showed a significant efficacy in reducing Lp(a) [weighted mean difference (WMD): -20.10%, 95% confidence interval (CI): -25.59% to -14.61%] compared with placebo. In the drug type subgroup analyses, although the efficacy of evolocumab was slightly low (WMD: -19.98%, 95% CI: -25.23% to -14.73%), there was no difference with alirocumab (WMD: -20.54%, 95% CI: -30.07% to -11.02%). In the treatment duration subgroup analyses, the efficacy of the 12-week duration group (WMD: -17.61%, 95% CI: -23.84% to -11.38%) was lower than in the group of ≥ 24 weeks' duration (WMD: -22.81%, 95% CI: -31.56% to -14.07%). In the participants' characteristics subgroup analyses, the results showed that no differential effect of alirocumab/evolocumab therapy on plasma Lp(a) concentrations was observed (heterozygous FH [HeFH] WMD: -20.07%, 95% CI: -26.07% to -14.08%; homozygous FH [HoFH] WMD: -20.04%, 95% CI: -36.31% to -3.77%). Evaluation of all-cause adverse events (AEs) between alirocumab/evolocumab groups and placebo groups [relative risk (RR): 1.05, 95% CI: 0.98-1.12] implied no obvious difference between the 2 groups. Conclusions: Anti-PCSK9 drugs (alirocumab and evolocumab) may be effective as therapy for reducing serum Lp(a) levels in FH, and no differences were observed in treatment durations, participant characteristics, and other aspects of the 2 types of PCSk9 inhibitors. However, further experimental studies and RCTs are warranted to clarify the mechanism of PSCK9 inhibitors to lowering Lp(a) concentrations in FH.
... Hemoglobin A1C predicts subclinical atherosclerosis [254]. Hypertension* Essential, secondary, or primary aldosteronism [154] Blood pressure is safest at or below 120/70 mm Hg at any age [255][256][257][258] Elevated Lipoprotein (a) [259][260][261][262][263][264]* Levels > 75 Nmol/L [265][266][267][268][269] Elevated levels are likely as common as 20% of the population. A major contributor to ASCVD and calcific aortic stenosis. ...
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Atherosclerotic cardiovascular disease (ASCVD) is epidemic throughout the world and is etiologic for such acute cardiovascular events as myocardial infarction, ischemic stroke, unstable angina, and death. ASCVD also impacts risk for dementia, chronic kidney disease peripheral arterial disease and mobility, impaired sexual response, and a host of other visceral impairments that adversely impact the quality and rate of progression of aging. The relationship between low-density lipoprotein cholesterol (LDL-C) and risk for ASCVD is one of the most highly established and investigated issues in the entirety of modern medicine. Elevated LDL-C is a necessary condition for atherogenesis induction. Basic scientific investigation, prospective longitudinal cohorts, and randomized clinical trials have all validated this association. Yet despite the enormous number of clinical trials which support the need for reducing the burden of atherogenic lipoprotein in blood, the percentage of high and very high-risk patients who achieve risk stratified LDL-C target reductions is low and has remained low for the last thirty years. Atherosclerosis is a preventable disease. As clinicians, the time has come for us to take primordial prevention more seriously. Despite a plethora of therapeutic approaches, the large majority of patients at risk for ASCVD are poorly or inadequately treated, leaving them vulnerable to disease progression, acute cardiovascular events, and poor aging due to loss of function in multiple visceral organs. Herein we discuss the need to greatly intensify efforts to reduce risk, decrease disease burden, and provide more comprehensive and earlier risk assessment to optimally prevent ASCVD and its complications. Evidence is presented to support that treatment should aim for far lower goals in cholesterol management, should take into account many more factors than commonly employed today and should begin significantly earlier in life.
... Recently, lipoprotein(a) [Lp(a)] has been recognized as a novel independent risk factor for the incidence of CHD [3][4][5][6][7], which is consisted of a low-density lipoprotein-like particle and apolipoprotein B100, with apolipoprotein(a) [apo(a)], the characteristic protein of Lp(a), covalently binding to it via a disulfide binding [8]. Compositionally, Lp(a) shows higher pathogenicity compared with LDLcholesterol (LDL-C) in CHD due to the presence of apo(a), which is regarded as the major causative factor of atherosclerosis, thrombosis and inflammation [9]. ...
... In addition, we found that unplanned revascularization drove the composite outcome, which was to some extent in agreement with the former researchers [12,15]. This could be explained by the pathogenicity of Lp(a), which included atherosclerosis, inflammation and thrombosis [9]. Another possible reason may be that patients with high-Lp(a) levels were more likely to have lesions in multiple coronary arteries, and the lesions usually need to be treated several times. ...
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Background: Whether lipoprotein(a) [Lp(a)] is associated with recurrent cardiovascular events (RCVEs) still remains controversial. The present study aimed to investigate the prognostic value of Lp(a) for long-term RCVEs and each component of it in people with acute coronary syndrome (ACS). Methods: This multicenter, observational and retrospective study enrolled 765 ACS patients at 11 hospitals in Chengdu from January 2014 to June 2019. Patients were assigned to low-Lp(a) group [Lp(a) < 30 mg/dl] and high-Lp(a) group [Lp(a) ≥ 30 mg/dl]. The primary and secondary endpoints were defined as RCVEs and their elements, including all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke and unplanned revascularization. Results: Over a median 17-month follow-up, 113 (14.8%) patients presented with RCVEs were reported, among which we observed 57 (7.5%) all-cause deaths, 22 (2.9%) cases of nonfatal stroke, 13 (1.7%) cases of nonfatal MI and 33 (4.3%) cases of unplanned revascularization. The incidences of RCVEs and revascularization in the high-Lp(a) group were significantly higher than those in the low-Lp(a) group (P < 0.05), whereas rates of all-cause death, nonfatal stroke and nonfatal MI were not statistically different (P > 0.05). Kaplan-Meier analysis also revealed the same trend. Multivariate Cox proportional hazards analysis showed that 1-SD increase of Lp(a) was independently associated with both the primary endpoint event [hazard ratio (HR), 1.285 per 1-SD; 95% confidence interval (CI), 1.112-1.484; P < 0.001] and revascularization (HR, 1.588 per 1-SD; 95% CI, 1.305-1.932; P < 0.001), but not with the other secondary events. Conclusion: Increased Lp(a) is an independent predictor of RCVEs and unplanned revascularization in patients with ACS.
Chapter
Cardiovascular disease (CVD) is the number one killer of both men and women in the United States (U.S.) and throughout the world, accounting for one-third of all deaths. In order to curb CVD, it is important that nurses and other health-care providers partner with patients to prevent or reduce CVD risk factors. Risk factors are biological characteristics or exposures to certain environmental conditions that increase a person’s statistical risk of developing atherosclerotic cardiovascular disease (ASCVD). Some risk factors cannot be modified, such as age, sex, family history of premature ASCVD, and race and ethnicity. Genetic variants have also been linked to ASCVD as well as environmental factors that contribute to epigenetic modifications of DNA. Major risk factors that can be managed are dyslipidemia, hypertension, diabetes metabolic syndrome (MetS), and chronic kidney disease (CKD). Recently appreciated risk factors in women are adverse pregnancy outcomes (APOs), such as preeclampsia and gestational hypertension, which can increase a woman’s risk of developing CVD later in life. Other risk factors are behavioral or pertain to lifestyle, such as tobacco use, physical inactivity, poor nutritional practices, inadequate sleep, and stress. These will be discussed in other chapters.
Chapter
There are innumerable risk factors for cardiovascular disease (CVD), many of which still need to be discovered and studied. In prior chapters, traditional risk factors with strong evidence for their risk to CVD and mechanisms were presented. This chapter will explore some of the emerging risk factors that have been researched over the past several years and are continuing to be under study as well as their impact on the development of cardiovascular disease. These are lipoprotein (a), apolipoprotein B, inflammatory markers, transgender health issues, and virus exposure.