Is Lp(a) ready for prime time use in the clinic? A pros-and-cons debate

Lipoprotein (a) (Lp(a)) is a cholesterol-rich lipoprotein known since 1963. In spite of extensive research on Lp(a), there are still numerous gaps in our knowledge relating to its function, biosynthesis and catabolism. One reason for this might be that apo(a), the characteristic glycoprotein of Lp(a), is expressed only in primates. Results from experiments using transgenic animals therefore may need verification in humans. Studies on Lp(a) are also handicapped by the great number of isoforms of apo(a) and the heterogeneity of apo(a)-containing fractions in plasma. Quantification of Lp(a) in the clinical laboratory for a long time has not been standardized. Starting from its discovery, reports accumulated that Lp(a) contributed to the risk of cardiovascular disease (CVD), myocardial infarction (MI) and stroke. Early reports were based on case control studies but in the last decades a great deal of prospective studies have been published that highlight the increased risk for CVD and MI in patients with elevated Lp(a). Final answers to the question of whether Lp(a) is ready for wider clinical use will come from intervention studies with novel selective Lp(a) lowering medications that are currently underway. This article expounds arguments for and against this proposition from currently available data

L’influence des relations familiales et sociales sur la consommation de médicaments psychotropes chez les personnes âgées

Les psychotropes occupent le deuxième rang dans la consommation de médicaments chez les personnes âgées. L'objectif de cette étude est de vérifier un modèle explicatif de la consommation de psychotropes dans cette population. Notre principale hypothèse est que la qualité des relations qu'entretient une personne âgée avec autrui, et particulièrement avec ses enfants, a une influence directe sur son bien-être psychologique, lequel a une influence directe sur la non-consommation de psychotropes. Une enquête a été réalisée auprès d'un échantillon de 500 personnes âgées de 65 à 84 ans, vivant à domicile. Au cours des trois mois précédant l'entrevue, 31,8 % des répondants ont consommé des psychotropes. Les données empiriques n'ayant pas permis de vérifier le modèle théorique retenu, des analyses multivariées ont conduit à l'élaboration d'un modèle explicatif de la consommation qui met en évidence que le bien-être psychologique et la santé sont les meilleurs prédicteurs de cette consommation. Un bien-être psychologique élevé diminue la consommation alors qu'un mauvais état de santé l'augmente. Les relations sociales influencent directement le bien-être psychologique alors que les relations familiales ont un effet de moindre importance. Le modèle explicatif proposé explique 13 % du phénomène de la consommation de psychotropes chez les personnes âgées.Psychotropic drugs are the second most commonly used medication by Quebec's elderly. The objective of this study is to test a theoretical model of psychotropic drug use in the elderly. The principal hypothesis is that the quality of relationships the elderly person has with others, particularly with his or her children, has a direct influence on his or her psychological well-being, which, in turn, directly affects the consumption of psychotropic agents. A survey was conducted on a sample of 500 elderly people, aged 65-84 years, living at home. 31.8% of the respondents used psychotropic drugs during the three-month period preceding the interview. Path analysis led to the elaboration of a modified model for the consumption of psychotropic drugs by the elderly which indicates that the best predictors of consumption are both the psychological well-being and the state of health of the individual. More elevated is the psychological well-being, less is the consumption of psychotropic drugs, whereas poor health condition increases it. The quality of an individual's social relationships has a direct influence on his or her psychological well-being, whereas family relationships are of lesser importance. Our model accounts for 13% of the predictors of psychotropic consumption by the elderly

The Effects of Tamoxifen on Plasma Lipoprotein(a) Concentrations: Systematic Review and Meta-Analysis

Introduction: Tamoxifen is a selective estrogen receptor modulator widely used in the treatment of breast cancer. Tamoxifen therapy is associated with reduced circulating low-density lipoprotein cholesterol and increased triglycerides, but its effects on other lipids are less-well studied. Aims: We aimed to investigate the effect of tamoxifen on circulating concentrations of lipoprotein(a) (Lp(a)) through systematic review and meta-analysis of available randomized controlled trials (RCTs) and observational studies. Methods: This study was registered in the PROSPERO database (CRD42016036890). Scopus, Medline and EMBASE were searched from inception until 22nd March 2016 to identify studies investigating the effect of tamoxifen on Lp(a) values in humans. Results: Meta-analysis of 5 studies with 284 participants suggested a significant reduction of Lp(a) levels following tamoxifen treatment (weighted mean difference [WMD]: -3.53 mg/dL, 95% confidence interval [CI]: -6.53, -0.53, p=0.021). When studies were categorized according tamoxifen dose, there was a significant effect in the subset of studies with administered doses ≥20 mg/day (WMD: -5.05 mg/dL, 95% CI: -7.86, -2.23, p<0.001), but not in the subset with doses <20 mg/day (WMD: -1.41 mg/dL, 95% CI: -5.13, 2.31, p=0.458). With respect to duration of treatment, a greater effect was observed in subgroup of studies administering tamoxifen for <12 weeks (WMD: -4.01 mg/dL, 95% CI: -7.84, -0.18, p=0.04) versus the subgroup of studies lasting ≥12 weeks (WMD: -2.48 mg/dL, 95% CI: -5.50, 0.53, p=0.107). Conclusions: Meta-analysis suggested a significant reduction of Lp(a) levels following tamoxifen treatment. Further well-designed trials are required to validate these results

Lp(a) and the Risk for Cardiovascular Disease: Focus on the Lp(a) Paradox in Diabetes Mellitus

Lipoprotein(a) (Lp(a)) is one of the strongest causal risk factors of atherosclerotic disease. It is rich in cholesteryl ester and composed of apolipoprotein B and apo(a). Plasma Lp(a) levels are determined by apo(a) transcriptional activity driven by a direct repeat (DR) response element in the apo(a) promoter under the control of (HNF)4α Farnesoid-X receptor (FXR) ligands play a key role in the downregulation of APOA expression. In vitro studies on the catabolism of Lp(a) have revealed that Lp(a) binds to several specific lipoprotein receptors; however, their in vivo role remains elusive. There are more than 1000 publications on the role of diabetes mellitus (DM) in Lp(a) metabolism; however, the data is often inconsistent and confusing. In patients suffering from Type-I diabetes mellitus (T1DM), provided they are metabolically well-controlled, Lp(a) plasma concentrations are directly comparable to healthy individuals. In contrast, there exists a paradox in T2DM patients, as many of these patients have reduced Lp(a) levels; however, they are still at an increased cardiovascular risk. The Lp(a) lowering mechanism observed in T2DM patients is most probably caused by mutations in the mature-onset diabetes of the young (MODY) gene and possibly other polymorphisms in key transcription factors of the apolipoprotein (a) gene (APOA)

Hyper- and Dyslipoproteinemias

Hyper- and dyslipoproteinemias are hallmarks for atherosclerosis, cardiovascular diseases, and stroke. Under normal physiological conditions, lipids are transported by three major lipoprotein classes: triglyceride-rich (chylomicrons, VLDL), cholesterol-rich (LDL, Lp(a)), and protein-rich (HDL) lipoproteins. Dietary fat after absorption is incorporated into chylomicrons that are catabolized in the “exogenous pathway.”� The endogenous pathway of lipoproteins starts with the secretion of VLDL from liver, the hydrolysis by lipoprotein lipase, and the formation of the final product, LDL. LDL are thought to deliver cholesterol to peripheral organs via the LDL receptor. A low LDL-receptor activity is characteristic for high plasma LDL, and vice versa. Due to their relatively long residence time in circulation, LDL are modified by oxidative stress and high glucose levels. These particles cannot bind to the LDL receptor and must be cleared from circulation by “scavenger receptors”� of macrophages. An overload of such pathogenic lipoproteins gives rise to foam cell formation, atherosclerotic plaques, and occlusion of arteries. HDL on the other hand are the good guys as they take up cholesterol from periphery and transport them to the liver (reverse cholesterol transport). The liver converts this fraction of cholesterol into bile acids that are secreted together with free cholesterol into bile. There exist additional very atherogenic lipoproteins such as Lp(a), small dense LDL, or pre-β LDL. A derangement in the well-balanced lipoprotein metabolism leads to hyper-and dyslipoproteinemias, metabolic syndrome, and atherosclerosis

FGF19 signaling cascade suppresses APOA gene expression

The aroA locus of the Gram- pathogen Dichelobacter nodosus, which encodes 5-enolpyruvylshikimate 3-phosphate (EPSP) synthase, has been sequenced and expressed in Escherichia coli. The gene is located on a 1.48-kb DraI-HindIII fragment located directly upstream and in opposite transcriptional orientation to the gene encoding the fimbrial structural subunit. The deduced open reading frame is 1329 nucleotides in length, which encodes a protein of 443 amino acids (aa) with a calculated M(r) of 47,413, which was visualized in E. coli minicells, under the control of its native promoter. This derived aa sequence displays significant similarities with the sequences of the aroA gene products from a variety of microorganisms

Patients with coronary slow flow phenomenon demonstrate normal myocardial blood flow and arterial wave reflection between acute episodes

Background: Patients with coronary slow flow ( CSF) present with a syndrome ( often recurrent) of resting angina with no significant coronary stenoses. The nature of myocardial blood flow ( MBF), MBF reserve and systemic arterial characteristics may contribute to symptoms in these patients but this has not been examined previously. This study sought to measure MBF, arterial stiffness and wave reflection in patients with CSF and controls

Development and pilot test of a peer-support based Cardiac-Diabetes Self-Management Program: A study protocol

Background: People with cardiac disease and type 2 diabetes have higher hospital readmission rates (22%) compared to those without diabetes (6%). Self-management is an effective approach to achieve better health outcomes; however there is a lack of specifically designed programs for patients with these dual conditions. This project aims to extend the development and pilot test of a Cardiac-Diabetes Self-Management Program incorporating user-friendly technologies and the preparation of lay personnel to provide follow-up support. Methods/Design: A randomised controlled trial will be used to explore the feasibility and acceptability of the Cardiac-Diabetes Self-Management Program incorporating DVD case studies and trained peers to provide follow-up support by telephone and text-messaging. A total of 30 cardiac patients with type 2 diabetes will be randomised, either to the usual care group, or to the intervention group. Participants in the intervention group will received the Cardiac-Diabetes Self-Management Program in addition to their usual care. The intervention consists of three face-to-face sessions as well as telephone and text-messaging follow up. The face-to-face sessions will be provided by a trained Research Nurse, commencing in the Coronary Care Unit, and continuing after discharge by trained peers. Peers will follow up patients for up to one month after discharge using text messages and telephone support. Data collection will be conducted at baseline (Time 1) and at one month (Time 2). The primary outcomes include self-efficacy, self-care behaviour and knowledge, measured by well established reliable tools. Discussion: This paper presents the study protocol of a randomised controlled trial to pilot evaluates a Cardiac-Diabetes Self-Management program, and the feasibility of incorporating peers in the follow-ups. Results of this study will provide directions for using such mode in delivering a self-management program for patients with both cardiac condition and diabetes. Furthermore, it will provide valuable information of refinement of the intervention program. Trial Registration Number ACTRN12611000086965Health and Social Development, Faculty of (Okanagan)Non UBCReviewedFacult

Molecular, Population, and Clinical Aspects of Lipoprotein(a): A Bridge Too Far?

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 properties and by a lack of suitable animal models. Furthermore, a lack of standardized assays to measure Lp(a) and no universal consensus on optimal plasma levels remain significant obstacles. In addition, there are currently no approved specific therapies that target and lower elevated plasma Lp(a), although there are recent but limited clinical outcome data suggesting benefits of such reduction. Despite this, international guidelines now recognize elevated Lp(a) as a risk enhancing factor for risk reclassification. This review summarises the current literature on Lp(a), including its discovery and recognition as an atherosclerotic cardiovascular disease risk factor, attempts to standardise analytical measurement, interpopulation studies, and emerging therapies for lowering elevated Lp(a) levels