Specific Lp Research Articles

Joint sparse optimization: lower-order regularization method and application in cell fate conversion

Multiple measurement signals are commonly collected in practical applications, and joint sparse optimization adopts the synchronous effect within multiple measurement signals to improve model analysis and sparse recovery capability. In this paper, we investigate the joint sparse optimization problem via ℓp,q regularization ( 0⩽q⩽1⩽p ) in three aspects: theory, algorithm and application. In the theoretical aspect, we introduce a weak notion of joint restricted Frobenius norm condition associated with the ℓp,q regularization, and apply it to establish an oracle property and a recovery bound for the ℓp,q regularization of joint sparse optimization problem. In the algorithmic aspect, we apply the well-known proximal gradient algorithm to solve the ℓp,q regularization problems, provide analytical formulas for proximal subproblems of certain specific ℓp,q regularizations, and establish the global convergence and linear convergence rate of the proximal gradient algorithm under some mild conditions. More importantly, we propose two types of proximal gradient algorithms with the truncation technique and the continuation technique, respectively, and establish their convergence to the ground true joint sparse solution within a tolerance relevant to the noise level and the recovery bound under the assumption of restricted isometry property. In the aspect of application, we develop a novel method, based on joint sparse optimization with lower-order regularization and proximal gradient algorithm, to infer the master transcription factors for cell fate conversion, which is a powerful tool in developmental biology and regenerative medicine. Numerical results indicate that the novel method facilitates fast identification of master transcription factors, give raise to the possibility of higher successful conversion rate and in the hope of reducing biological experimental cost.

Lipoprotein(a): from Causality to Treatment.

This paper reviews the evidence why lipoprotein(a) (Lp(a)) is a causal risk factor for cardiovascular disease and how high Lp(a) concentrations should be managed now and with an outlook to the future. No optimal and widely available animal models exist to study the causality of the association between Lp(a) and cardiovascular disease. This has been a major handicap for the entire field. However, genetic studies turned the page. Already in the early 1990s, the principle of Mendelian randomization studies was applied for the first time ever (even if they were not named so at that time). Genetic variants of the LPA gene such as the apolipoprotein(a) isoform size, the number and sum of kringle IV repeats and later single nucleotide polymorphisms are strongly associated with life-long exposure to high Lp(a) concentrations as well as cardiovascular outcomes. This evidence provided a basis for the development of specific Lp(a)-lowering drugs that are currently in clinical testing phase. Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease. With the specific Lp(a)-lowering therapies, we might get tools to fight this common risk factor in case the outcome trials will be positive.

The influence of lipoproteina(a) on cardio-vascular diseases

Introduction
 The current evidence from 2022 published by European Atherosclerosis Society brings the importance of the level of lipoprotein(a) and its influence on the human health. Especially atherosclerotic cardio-vascular events such as myocardial infarction, heart failure, stroke, atherosclerosis are taken into account. They prove, that the associations between the level of Lp(a) is linear with the occurrence of cardio-vascular events. High level of Lp(a), may contribute to the aortic stenosis, cause has pro-inflammatory and pro-atherosclerotic properties. The newest finding demonstrate that Lp(a) has no link with venous thrombosis. Nonetheless, very low level of may contribute with type 2 diabetes.
 It is recommended to measure the level of lipoprotein(a) at least once in adults to search the patients with higher value than norm. Even at low level of LDL, high Lp(a) is a risk factor for ASCVD. It brings the clinical importance of early detection of potential cardio-vascular diseases and introduction of management. The newest statement form EAS also brings promising possibilities due to specific Lp(a)-lowering therapies is in phase II/III trials.
 
 Aim of the study
 The following paper aims to present a review of the current knowledge about the influence of the level of Lp(a) on cardio-vascular disease and seeks to enhance knowledge and promote effective management of this prevalent condition.
 The primary goal is to promote the current problem to health care workers with up-to-date information to facilitate early recognition of cardiovascular events.
 
 Materials and methods
 This article presents the current state of knowledge of lipoprotein(a) found in various scientific articles.
 The following English keywords and its Polish equivalents were used to search Google Scholar's medical databases: lipoprotein(a), cardio-vascular disease, cardiovascular risk, aortic stenosis. The articles most pertinent to the subject have been chosen.

Changes in Lipoprotein(a) Levels in People after ST Elevation Myocardial Infarction-The STEMI-Lipids Study.

Lipoprotein(a) (Lp(a)) is considered an independent risk factor for cardiovascular diseases. The plasma concentration of Lp(a) is largely genetically determined but varies over a wide range within the population. This study investigated changes in Lp(a) levels after an acute myocardial infarction. Patients who underwent coronary angiography due to an ST elevation myocardial infarction were enrolled (n = 86), and Lp(a) levels were measured immediately after the intervention, one day, two days, and at a post-discharge follow-up visit at 3 to 6 months after the acute myocardial infarction. Median Lp(a) levels increased from a median of 7.9 mg/dL (3.8-37.1) at hospital admission to 8.4 mg/dL (3.9-35.4) on the following day, then to 9.3 mg/dL (3.7-39.1) on day two (p < 0.001), and to 11.2 mg/dL (4.4-59.6) at the post-discharge follow-up (p < 0.001). Lp(a) levels were the lowest during the acute myocardial infarction and started to increase significantly immediately thereafter, with the highest levels at the post-discharge follow-up. The moderate but significant increase in Lp(a) in people with acute myocardial infarction appears to be clinically relevant on an individual basis, especially when specific Lp(a) cut-off levels are supposed to determine the initiation of future treatment. Hence, a repeated measurement of Lp(a) after myocardial infarction should be performed.

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.

This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.

How should public health recommendations address Lp(a) measurement, a causative risk factor for cardiovascular disease (CVD)?

Background and aimsElevated concentrations of Lipoprotein (a) [Lp(a)] is an inherited, causal risk factor for atherosclerotic cardiovascular disease (ASCVD). This study aims to investigate the clinical utility for patients, and the economic benefit to healthcare systems and society of measuring Lp(a) concentrations more widely today. MethodsWe conducted a structured literature review to identify the economic and health benefits and costs of measuring the Lp(a) concentration, potential barriers hindering the uptake of the measure, and potential solutions to address them. These findings were then discussed in an advisory board attended by experts and patient organisations. ResultsIt was found that if Lp(a) concentration is measured more widely today, patients, healthcare system and society would experience clinical and economic benefits even before specific Lp(a) lowering pharmacological treatments become available. Furthermore, a wider uptake of the Lp(a) measurement would support the development of epidemiological data. ConclusionsFor Lp(a) measurement to be more widely used, key barriers which are hindering its uptake need to be addressed. These include i) the perception that the measure may have limited clinical value, ii) lack of awareness on Lp(a), iii) lack of data on the CV benefit of reducing Lp(a), iv) technical and clinical guidelines barriers, and v) healthcare system barriers. Scientific communities and industry should collaborate to address technical challenges and deficiencies in clinical guidelines. However, policy intervention will be crucial for national ASCVD plans to acknowledge the importance of Lp(a).

STUDY OF THE QUALIT Y OF PHARMACEUTICAL INFORMATION FOR PATIENTS FROM THE PERSPECTIVE OFTHE PROPER USE OF ANTI-ASTHMATIC DRUGS

RELEVANCE. Bronchial asthma, along with cardiovascular and oncological diseases, is one of the three most common chronic non- communicable diseases. For the most part, anti-asthmatic drugs (LP) are presented in the form of aerosols, powders, solutions for inhalation and other dosage forms intended for administration directly into the human respiratory tract. It is obvious that misunderstanding of the method of application and / or insufficient effectiveness of LP due to improper use can lead to a decrease in patients’ adherence to the prescribed therapy. In this regard, the availability of pharmaceutical information in the instructions becomes important, i.e. the more accessible the information in the instructions is to the patient, the higher the probability of proper use of the drug, maintaining patient compliance and preserving the patient’s quality of life. PURPOSE. The aim of the study was to analyze the completeness of pharmaceutical information provided in the instructions for the medical use of anti-asthmatic drugs (LP) and on the websites of manufacturing companies, from the standpoint of patients’ compliance with the rules for the use of LP. The main objectives of the analysis were: identification of the proportion of anti- asthmatic drugs that have a detailed scheme of use in the instructions; analysis of the instructions of anti-asthmatic drugs from the position of having indications of additional features of the use / use of drugs; analysis of instructions for anti-asthmatic drugs, the use of which is possible for groups of patients with physical or cognitive disabilities; identification of the share of companies producing anti-asthmatic drugs that support patients by conducting a specialized consulting service on the use of drugs. METHODS. The assessment of the quality of pharmaceutical information for patients was carried out on the basis of an analysis of 165 instructions for the medical use of pharmacotherapeutic groups of drugs designated in GINA-2021 (Global Initiative for Asthma-2021) and Federal Clinical Guidelines for the Treatment of Bronchial Asthma of the Russian Respiratory Society (2019) as anti-asthmatic drugs. The analysis was also carried out in relation to the information content of the websites of anti-asthmatic LP manufacturers, additionally, by creating a direct search query, the presence of a private page on the Internet for specific LP was determined. In the course of the research, methods of logical, comparative analysis, as well as generalization and grouping were used. To process the results obtained, the Excel computer program of the Microsoft Office 10 package was used. RESULTS. As a result of the analysis, it was revealed that the vast majority of anti-asthmatic drugs of all the studied pharmacotherapeutic groups are intended for administration directly into the respiratory tract, the article presents the results of a study on the ratio of inhaled and non-inhaled dosage forms in the context of the analyzed pharmacotherapeutic groups. The article presents data on the proportion of anti-asthmatic drugs that have a detailed description in the instructions in addition to the standard method of application (figure, diagram, pictogram) the method of introduction / use of LP. The fact of the absence of a detailed method of application in the instructions of various pharmacotherapeutic groups has been established. The results of the analysis of the number of instructions with the additional properties of LP indicated in them, allowing the use of LP data in patients with physical or cognitive characteristics (limitations), are presented. The number of companies producing anti-asthmatic drugs that have posted detailed information for consumers regarding the use of these drugs on their websites, as well as the number of drugs that have their own website, has been revealed. CONCLUSION. The information in the instructions for the medical use of anti-asthmatic drugs and on the official websites of the manufacturing companies (holders of registration certificates) of the studied drugs is not always exhaustive in terms of the use of inhaled dosage forms, which does not fully ensure the safe and effective receipt of anti-asthmatic pharmacotherapy. According to the authors, improving the quality of information for patients about the rules of using drugs for the treatment of bronchial asthma will simplify the use of dosage forms specific for its therapy, increase patients’ adherence to prescribed pharmacotherapy, reduce the risks from insufficient effectiveness of anti-asthmatic pharmacotherapy and preserve the quality of life of patients associated with the disease.

Lipoprotein(a) and Cardiovascular Disease: A Missing Link for Premature Atherosclerotic Heart Disease and/or Residual Risk.

Lipoprotein(a) or lipoprotein "little a" [Lp(a)] is an under-recognized causal risk factor for cardiovascular (CV) disease (CVD), including coronary atherosclerosis, aortic valvular stenosis, ischemic stroke, heart failure, and peripheral arterial disease. Elevated plasma Lp(a) (≥50 mg/dL or ≥100 nmol/L) is commonly encountered in almost 1 in 5 individuals and confers a higher CV risk compared with those with normal Lp(a) levels, although such normal levels have not been generally agreed upon. Elevated Lp(a) is considered a cause of premature and accelerated atherosclerotic CVD. Thus, in patients with a positive family or personal history of premature coronary artery disease (CAD), Lp(a) should be measured. However, elevated Lp(a) may confer increased risk for incident CAD even in the absence of a family history of CAD, and even in those who have guideline-lowered LDL cholesterol (<70 mg/dL) and continue to have a persisting CV residual risk. Thus, measurement of Lp(a) will have a significant clinical impact on the assessment of atherosclerotic CVD risk, and will assume a more important role in managing patients with CVD with the advent and clinical application of specific Lp(a)-lowering therapies. Conventional therapeutic approaches like lifestyle modification and statin therapy remain ineffective at lowering Lp(a). Newer treatment modalities, such as gene silencing via RNA interference with use of antisense oligonucleotide(s) or small interfering RNA molecules targeting Lp(a), seem very promising. These issues are herein reviewed, accumulated data are scrutinized, meta-analyses and current guidelines are tabulated, and Lp(a)-related CVDs and newer therapeutic modalities are pictorially illustrated.

Docking to a Basic Helix Promotes Specific Phosphorylation by G1-Cdk1.

Cyclins are the activators of cyclin-dependent kinase (CDK) complex, but they also act as docking scaffolds for different short linear motifs (SLiMs) in CDK substrates and inhibitors. According to the unified model of CDK function, the cell cycle is coordinated by CDK both via general CDK activity thresholds and cyclin-specific substrate docking. Recently, it was found that the G1-cyclins of S. cerevisiae have a specific function in promoting polarization and growth of the buds, making the G1 cyclins essential for cell survival. Thus, while a uniform CDK specificity of a single cyclin can be sufficient to drive the cell cycle in some cells, such as in fission yeast, cyclin specificity can be essential in other organisms. However, the known G1-CDK specific LP docking motif, was not responsible for this essential function, indicating that G1-CDKs use yet other unknown docking mechanisms. Here we report a discovery of a G1 cyclin-specific (Cln1,2) lysine-arginine-rich helical docking motif (the K/R motif) in G1-CDK targets involved in the mating pathway (Ste7), transcription (Xbp1), bud morphogenesis (Bud2) and spindle pole body (Spc29, Spc42, Spc110, Sli15) function of S. cerevisiae. We also show that the docking efficiency of K/R motif can be regulated by basophilic kinases such as protein kinase A. Our results further widen the list of cyclin specificity mechanisms and may explain the recently demonstrated unique essential function of G1 cyclins in budding yeast.

Treatment and prevention of lipoprotein(a)-mediated cardiovascular disease: the emerging potential of RNA interference therapeutics.

Lipid- and lipoprotein-modifying therapies have expanded substantially in the last 25 years, resulting in reduction in the incidence of major adverse cardiovascular events. However, no specific lipoprotein(a) [Lp(a)]-targeting therapy has yet been shown to reduce cardiovascular disease risk. Many epidemiological and genetic studies have demonstrated that Lp(a) is an important genetically determined causal risk factor for coronary heart disease, aortic valve disease, stroke, heart failure, and peripheral vascular disease. Accordingly, the need for specific Lp(a)-lowering therapy has become a major public health priority. Approximately 20% of the global population (1.4 billion people) have elevated levels of Lp(a) associated with higher cardiovascular risk, though the threshold for determining ‘high risk’ is debated. Traditional lifestyle approaches to cardiovascular risk reduction are ineffective at lowering Lp(a). To address a lifelong risk factor unmodifiable by non-pharmacological means, Lp(a)-lowering therapy needs to be safe, highly effective, and tolerable for a patient population who will likely require several decades of treatment. N-acetylgalactosamine-conjugated gene silencing therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotide targeting LPA, are ideally suited for this application, offering a highly tissue- and target transcript-specific approach with the potential for safe and durable Lp(a) lowering with as few as three or four doses per year. In this review, we evaluate the causal role of Lp(a) across the cardiovascular disease spectrum, examine the role of established lipid-modifying therapies in lowering Lp(a), and focus on the anticipated role for siRNA therapeutics in treating and preventing Lp(a)-related disease.

Contemporary perspectives on the genetics and clinical use of lipoprotein(a) in preventive cardiology.

The pathogenicity of lipoprotein(a) [Lp(a)] as a risk factor for atherosclerotic cardiovascular disease (ASCVD) is well evidenced and recognized by international consensus-based guidelines. However, the measurement of Lp(a) is not routine clinical practice. Therapeutic agents targeting Lp(a) are now progressing through randomised clinical trials, and it is timely for clinicians to familiarize themselves with this complex and enigmatic lipoprotein particle. Recent developments in the understanding of genetic influences on the structure, plasma concentration and atherogenicity of Lp(a) have contextualized its clinical relevance. Mendelian randomization studies have enabled estimation of the contribution of Lp(a) to ASCVD risk. Genotyping individual patients with respect to Lp(a)-raising single nucleotide polymorphisms predicts ASCVD, but has not yet been shown to add value beyond the measurement of Lp(a) plasma concentrations, which should be done by Lp(a) isoform-independent assays capable of reporting in molar concentrations. Contemporary gene-silencing technology underpins small interfering RNA and antisense oligonucleotides, which are emerging as the leading Lp(a)-lowering therapeutic agents. The degree of Lp(a)-lowering required to achieve meaningful reductions in ASCVD risk has been estimated by Mendelian randomization, providing conceptual support. Measurement of Lp(a) in the clinical setting contributes to the assessment of ASCVD risk, and will become more important with the advent of specific Lp(a)-lowering therapies. Knowledge of an individual patient's genetic predisposition to increased Lp(a) appears to impart little or not additional clinical value beyond Lp(a) particle concentration.

Therapeutic Apheresis for Management of Lp(a) Hyperlipoproteinemia.

High lipoprotein(a) (Lp(a)) level is an independent cardiovascular risk factor with higher prevalence among patients with atherosclerotic cardiovascular disease (ASCVD). The actual problem is that most currently available lipid-lowering drugs are unable to abolish Lp(a) pathogenicity. Lipoprotein apheresis (LA) is an effective method for elimination of atherogenic lipoproteins, but it is approved only in some countries for treatment of elevated Lp(a) level in the presence of progressive ASCVD. In recent years, new studies on LA were published and the purpose of this review is to present the information on optimal management of Lp(a) hyperlipoproteinemia by LA in the modern era. Most clinical studies designed to treat Lp(a) hyperlipoproteinemia with different LA systems are small in size but demonstrate that the elimination of Lp(a) from bloodstream leads to reduction of inflammatory and prothrombotic process in a few months and to atherosclerotic plaques regression in 1.5years. Treatment with LA for 2 to 5years in terms of clinical trials and in real-world setting provides further evidence that Lp(a) reduction by 60-80% is associated with proportional decreasing of rate and risk of cardiovascular events. Specific Lp(a) apheresis is the only possible method that solely targets Lp(a). In most countries, non-specific LA is used for treatment Lp(a) hyperlipoproteinemia in very high-risk subjects with progressive ASCVD. PCSK9 inhibitors have only modest effect on significantly elevated Lp(a), whereas large population-based studies requested sustained and prolonged reduction of Lp(a) levels by 50-100mg/dL to gain proportional decreasing of major adverse cardiovascular events.

Lipoprotein(a): a genetic marker for cardiovascular disease and target for emerging therapies.

Lipoprotein(a) [Lp(a)] is an established cardiovascular risk factor, and growing evidence indicates its causal association with atherosclerotic disease because of the proatherogenic low-density lipoprotein (LDL)-like properties and the prothrombotic plasminogen-like activity of apolipoprotein(a) [apo(a)]. As genetics significantly influences its plasma concentration, Lp(a) is considered an inherited risk factor of atherosclerotic cardiovascular disease (ASCVD), especially in young individuals. Moreover, it has been suggested that elevated Lp(a) may significantly contribute to residual cardiovascular risk in patients with coronary artery disease and optimal LDL-C levels. Nonetheless, the fascinating hypothesis that lowering Lp(a) could reduce the risk of cardiovascular events - in primary or secondary prevention - still needs to be demonstrated by randomized clinical trials. To date, no specific Lp(a)-lowering agent has been approved for reducing the lipoprotein levels, and current lipid-lowering drugs have limited effects. In the future, emerging therapies targeting Lp(a) may offer the possibility to further investigate the relation between Lp(a) levels and cardiovascular outcomes in randomized controlled trials, ultimately leading to a new era in cardiovascular prevention. In this review, we aim to provide an updated overview of current evidence on Lp(a) as well as currently investigated therapeutic strategies that specifically address the reduction of the lipoprotein.

Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis

It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)Rx] directed to apo(a) (n = 7) or placebo (n = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477.3 ± 55.9 nmol/l in IONIS-APO(a)Rx and 362.1 ± 89.9 nmol/l in placebo. The mean± SD percentage change in Lp(a) for IONIS-APO(a)Rx was -69.3 ± 12.2% versus -5.4 ± 6.9% placebo (P < 0.0010) at day 85/92/99 and -15.6 ± 8.9% versus 3.2 ± 12.2% (P = 0.003) at day 190. Clot lysis times and coagulation/fibrinolysis-related biomarkers showed no significant differences between IONIS-APO(a)Rx and placebo at all time points. Clot lysis times were not affected by exogenously added Lp(a) at concentrations up to 200 nmol/l to plasma with very low (12.5 nmol/l) Lp(a) levels, whereas recombinant apo(a) had a potent antifibrinolytic effect. In conclusion, potent reductions of Lp(a) in patients with highly elevated Lp(a) levels do not affect ex vivo measures of fibrinolysis; the relevance of any putative antifibrinolytic effects of Lp(a) in vivo needs further study.

Reduction Of Plasma Lipoprotein(A) With Antisense Oligonucleotides In Human Subjects Does Not Affect Fibrinolysis

Background and Aims: Lipoprotein(a) [Lp(a)] is a causal genetic risk factor for atherothrombotic events. The homology between plasminogen and apolipoprotein(a) (apo(a)) suggests that Lp(a) might promote thrombosis through inhibition of fibrinolysis. This hypothesis is supported by in vitro studies but has not been tested in humans due to lack of specific Lp(a) lowering agents.

Loyalty program activity: make B2B customers buy more

Purpose Loyalty programs (LPs) in a business-to-business (B2B) context have been under-researched when compared to consumer markets. The purpose of this paper is to investigate if and to what extent the loyalty program activity (LPA) based on recency, frequency and monetary framework reflects the effectiveness of a specific LP. Design/methodology/approach Using the data obtained from 818 business customers enrolled in a LP, logistic regression models are run to find the impact of LPA on the company’s sales. Findings The results suggest that in a linear LP, the frequency of rewards impacts sales the most, compared to recency and amount of points redeemed. The intensity of a LPA is influencing the expected sales in a company. Research limitations/implications The current study is not focused on the redemption patterns and the value of the rewards offered in the program. Limitation of the study only to one country and in a single company does not allow to generalize presented findings. Practical implications Companies should focus their efforts on defining the best level of frequency rewards in their LPs. Reward timing should be considered as a factor that influences the change in customer purchasing behavior more than the amount of points accumulated. Originality/value The research provides empirical evidence to support the highest influence of frequency of rewards on sales, compared to recency and amount of points redeemed. This is one of the few LP studies conducted in the context of the B2B market.

Can Lp(a) Lowering Against Background Statin Therapy Really Reduce Cardiovascular Risk?

The association between elevated plasma levels of lipoprotein (a) [Lp(a)] and atherosclerotic cardiovascular disease (ASCVD) has been discussed for many years. Recent genetic findings have confirmed that elevated Lp(a) similar to elevated LDL-cholesterol (LDL-C) might be causally related to premature ASCVD. Lp(a) is relatively refractory to lifestyle interventions. The results of studies with statins and their possible effect on Lp(a) are conflicting. Specific Lp(a) apheresis is used as a treatment against background statin therapy and can decrease Lp(a). The purpose of this review is to discuss whether new drugs which decrease Lp(a) can prevent ASCVD and decrease ASCVD mortality when applied in addition to statins. Some new LDL-C-lowering drugs such as mipomersen and lomitapide decrease elevated Lp(a) in addition to statins but they have some unpleasant adverse effects. Recently, an antisense oligonucleotide against apo(a), AKCEA-APO(a)Rx, has been shown to selectively decrease Lp(a). The most recent advance in LDL-C lowering are PCSK9 inhibitors. Alirocumab and evolocumab do not only significantly reduce LDL-C on top of maximally tolerated statin therapy and prevent ASCVD events, but also further decrease Lp(a). There is no data to indicate whether mipomersen, lomitapide, or IONIS-APO(a)-LRx decrease ASCVD events and mortality. Conclusive evidence is still lacking as to whether the treatment with PCSK9 inhibitors against background statin therapy actually additionally reduces ASCVD risk due to the lowering of Lp(a) or simply due to lowering LDL-C to levels much lower than high-intensity statin treatment as monotherapy. Ongoing trials will probably provide an answer to these questions.

Lipoprotein(a) and mortality\u2014a\xa0high risk relationship

Lipoprotein(a) (Lp(a)) is an independent cardiovascular risk factor playing a causal role for atherosclerotic cardiovascular disease (ASCVD). Early or progressive ASCVD or a familial predisposition are key findings which can be associated with Lp(a)-hyperlipoproteinemia (Lp(a)-HLP). The German guideline for the indication of lipoprotein apheresis in patients with Lp(a)-HLP has proved to be of value to identify patients at highest risk, using the composite of a Lp(a) threshold >60 mg/dl (>120 nmol/l) and clinical ASCVD progression despite effective LDL-C lowering therapy. In particular for such patients it appears to be plausible that Lp(a)-associated risk would increase cardiovascular mortality as the most important part of total mortality in Western populations. By the majority of existing investigations an association of Lp(a) concentration on total or cardiovascular mortality was demonstrated. However, inconsistency in the findings between studies exists without a clear trend for any study feature to explain this. Genetic homogeneity of the population, long-term follow-up, and clinically guided selection of patients might be important to further clarify the impact of Lp(a) concentration on progression of ASCVD, and finally total or cardiovascular mortality. LDL and Lp(a) particles exhibit a mutual effect modification on related ASCVD risk. Therefore, LDL-C levels and concomitant LDL-C lowering treatment must be considered in this context. Prospective evaluation is needed to document that specific Lp(a)-lowering additional to targeted LDL-C lowering will in fact reduce cardiovascular or total mortality.

Specific Lp(a) apheresis: A tool to prove lipoprotein(a) atherogenicity

BackgroundAn elevated lipoprotein(a) (Lp(a)) level is observed in more than 30% of patients with stable ischemic heart disease (SIHD). We conducted an investigation of the effects of specific Lp(a) apheresis on the progression of atherosclerosis in SIHD patients with Lp(a) levels greater than 50 mg/dL. MethodsWe prospectively enrolled 15 patients diagnosed with SIHD based on symptom-driven coronary angiography findings, with Lp(a) ≥50 mg/dL and a low density lipoprotein cholesterol (LDL-C) ≤2.5 mmol/L, who were on long-term statin therapy. They underwent weekly Lp(a) apheresis using Lp(a) Lipopak® adsorption columns which contain monospecific sheep polyclonal antibodies against human Lp(a). Fifteen age and gender matched SIHD patients receiving atorvastatin monotherapy served as controls. At baseline and 18 months post-treatment, quantitative coronary angiography, intracoronary ultrasound with virtual histology and carotid ultrasound were performed. Lipid profile, including Lp(a), was measured at the scheduled visits, and before and after each apheresis procedure. Levels of high-sensitivity C-reactive protein (hsCRP), matrix metalloproteinases (MMP)-7 and 9, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 and 2 were determined at baseline and at the end of the study period. ResultsEach specific Lp(a) apheresis procedure was carried out with two adsorption columns resulting in an average acute decrease in Lp(a) levels of 75% (from 110 ± 22 to 29 ± 16 mg/dL) without significant changes in other plasma components. Lp(a) reduction over the course of 18 months was associated with a decrease in the mean percent diameter stenosis of 5.05% and an increase in minimal lumen diameter of 14%; the mean total atheroma volume was reduced by 4.60 mm3 (p < 0.05 for all). There was a decrease in absolute common carotid intima-media thickness in the Lp(a) apheresis group of 0.07 ± 0.15 mm both from baseline and compared with the control group (p = 0.01). Levels of hsCRP were reduced by 40% in patients on Lp(a) apheresis without significant changes in the levels of other biomarkers at the end of the study. ConclusionReduction of the atherosclerotic burden in coronary and carotid arteries was observed in patients treated with specific Lp(a) apheresis and statin over 18 months compared with statin therapy alone. These findings support the atherogenic role of Lp(a) and reinforce the need to assess the effects of Lp(a)-lowering on cardiovascular events and mortality.Trial Registration Clinicaltrials.gov (NCT02133807).

Lipoprotein(a) apheresis

Currently, different methods for extracorporeal elimination of atherogenic apolipoprotein B100 containing lipoprotein particles are used in clinical practice. Most of them effectively remove both lipoprotein(a) [Lp(a)] and LDL. The aim of this review is to highlight research describing the clinical advantages of specific Lp(a) immunosorption compared with other lipoprotein apheresis systems. Data on the utility of lipoprotein apheresis in patients with elevated Lp(a) level are limited. However, several longitudinal studies demonstrated improvement in cardiovascular outcomes when both Lp(a) and LDL cholesterol levels were decreased with different apheresis systems. The main limitation of these trials is the absence of a control group. First developed in 1991, studies on apheresis with a specific immunosorbent to Lp(a) were small and noncontrolled before 2000s. The only prospective controlled clinical trial utilising Lp(a) apheresis (Clinicaltrials.gov NCT02133807), demonstrated regression of coronary and carotid atherosclerosis when Lp(a) was removed weekly for 18 months. Lipoprotein apheresis usually affects multiple lipoproteins, and there are minimal data regarding the effect of specific removal of Lp(a) alone. There is a need for randomized controlled trial with specific Lp(a) apheresis to investigate its effect on cardiovascular outcomes.