Statin therapy in athletes and patients performing regular intense exercise - Position paper from the International Lipid Expert Panel (ILEP).

Acute and chronic physical exercises may enhance the development of statin-related myopathy. In this context, the recent (2019) guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) for the management of dyslipidemias recommend that, although individuals with dyslipidemia should be advised to engage in regular moderate physical exercise (for at least 30 min daily), physicians should be alerted with regard to myopathy and creatine kinase (CK) elevation in statin-treated sport athletes. However it is worth emphasizing that abovementioned guidelines, previous and recent ESC/EAS consensus papers on adverse effects of statin therapy as well as other previous attempts on this issue, including the ones from the International Lipid Expert Panel (ILEP), give only general recommendations on how to manage patients requiring statin therapy on regular exercises. Therefore, these guidelines in the form of the Position Paper are the first such an attempt to summary existing, often scarce knowledge, and to present this important issue in the form of step-by-step practical recommendations. It is critically important as we might observe more and more individuals on regular exercises/athletes requiring statin therapy due to their cardiovascular risk.

Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).

BACKGROUND AND AIMS: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. METHODS: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. RESULTS: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited. CONCLUSIONS: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed.

Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration.

BACKGROUND: The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. METHODS: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. CONCLUSIONS: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients.

Familial defective apolipoprotein B-100: A review.

Familial defective apolipoprotein B-100 (FDB) is an autosomal dominant genetic disorder of lipid metabolism associated with hyperlipidemia and elevated risk for atherosclerosis. FDB is caused by mutations in APOB reducing the binding affinity between apolipoprotein B-100 and the low-density lipoprotein receptor. Population studies suggest that approximately 0.1% of Northern Europeans and US Caucasians carries the R3500Q variant in APOB most commonly associated with FDB; in addition, the APOB R3500 W variant is known to make a significant contribution to familial hypercholesterolemia (FH) among East Asians. However, the elevation of plasma low-density lipoprotein cholesterol observed in FDB is frequently milder than that of FH due to mutations in LDLR, and FDB is subsequently underdiagnosed according to standard FH diagnostic criteria.

For debate: substituting placebo controls in long-term Alzheimer's prevention trials.

INTRODUCTION: Novel compounds with potential to attenuate or stop the progression of Alzheimer's disease (AD) from its presymptomatic stage to dementia are being tested in man. The study design commonly used is the long-term randomized, placebo-controlled trial (RPCT), meaning that many patients will receive placebo for 18 months or longer. It is ethically problematic to expose presymptomatic AD patients, who by definition are at risk of developing dementia, to prolonged placebo treatment. As an alternative to long-term RPCTs we propose a novel clinical study design, termed the placebo group simulation approach (PGSA), using mathematical models to forecast outcomes of presymptomatic AD patients from their own baseline data. Forecasted outcomes are compared with outcomes observed on candidate drugs, thus replacing a concomitant placebo group. METHODS: First models were constructed using mild cognitive impairment (MCI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. One outcome is the Alzheimer Disease Assessment Scale - cognitive subscale (ADAScog) score after 24 months, predicted in a linear regression model; the other is the trajectory over 36 months of a composite neuropsychological test score (Neuro-Psychological Battery (NP-Batt)), using a mixed model. Demographics and clinical, biological and neuropsychological baseline values were tested as potential predictors in both models. RESULTS: ADAScog scores after 24 months are predicted from gender, obesity, Functional Assessment Questionnaire (FAQ) and baseline scores of Mini-Mental State Examination, ADAScog and NP-Batt with an R2 of 0.63 and a residual standard deviation of 0.67, allowing reasonably precise estimates of sample means. The model of the NP-Batt trajectory has random intercepts and slopes and fixed effects for body mass index, time, apolipoprotein E4, age, FAQ, baseline scores of ADAScog and NP-Batt, and four interaction terms. Estimates of the residual standard deviation range from 0.3 to 0.5 on a standard normal scale. If novel drug candidates are expected to diminish the negative slope of scores with time, a change of 0.04 per year could be detected in samples of 400 with a power of about 80%. CONCLUSIONS: First PGSA models derived from ADNI MCI data allow prediction of cognitive endpoints and trajectories that correspond well with real observed values. Corroboration of these models with data from other observational studies is ongoing. It is suggested that the PGSA may complement RPCT designs in forthcoming long-term drug studies with presymptomatic AD individuals.

The triglyceride to high-density lipoprotein-cholesterol ratio in adolescence and subsequent weight gain predict nuclear magnetic resonance-measured lipoprotein subclasses in adulthood.

OBJECTIVE: To assess whether the fasting triglyceride-to-high-density lipoprotein (HDL)-cholesterol (TG/HDL) ratio in adolescence is predictive of a proatherogenic lipid profile in adulthood. STUDY DESIGN: A longitudinal follow-up of 770 Israeli adolescents 16 to 17 years of age who participated in the Jerusalem Lipid Research Clinic study and were reevaluated 13 years later. Lipoprotein particle size was assessed at the follow-up with proton nuclear magnetic resonance. RESULTS: The TG/HDL ratio measured in adolescence was strongly associated with low-density lipoprotein, very low-density lipoprotein (VLDL), and HDL mean particle size in young adulthood in both sexes, even after adjustment for baseline body mass index and body mass index change. The TG/HDL ratio measured in adolescence and subsequent weight gain independently predicted atherogenic small low-density lipoprotein and large VLDL particle concentrations (P < .001 in both sexes). Baseline TG/HDL and weight gain interacted to increase large VLDL concentration in men (P < .001). CONCLUSIONS: Adolescents with an elevated TG/HDL ratio are prone to express a proatherogenic lipid profile in adulthood. This profile is additionally worsened by weight gain.

Adiponectin and lipoprotein particle size.

OBJECTIVE: Adiponectin has been postulated to affect lipid and insulin signal transduction pathways. We evaluated the relationships of plasma adiponectin with lipoprotein mean particle size and subclass concentrations, independent of obesity and insulin sensitivity. RESEARCH DESIGN AND METHODS: A cross-sectional analysis of 884 young Israeli adults who participated in the population-based Jerusalem Lipid Research Clinic (LRC) study was conducted. Lipoprotein particle size was assessed using proton nuclear magnetic resonance. RESULTS: In multivariable linear regression models that included sex, BMI, waist circumference, homeostasis model assessment of insulin resistance, and leptin, adiponectin was associated with mean LDL size (standardized regression coefficient B = 0.20; P < 0.001), VLDL size (B = -0.12; P < 0.001), and HDL size (B = 0.06; P = 0.013). Adiponectin was inversely related to large VLDL (P < 0.001) but positively to small VLDL (P = 0.02), inversely related to small LDL (P < 0.006) but positively to large LDL (P < 0.001), and positively related to large HDL (P < 0.001) subclass concentrations. CONCLUSIONS: Adiponectin is favorably associated with lipoprotein particle size and subclass distribution independent of adiposity and insulin sensitivity.

Leptin, insulin, and obesity-related phenotypes: genetic influences on levels and longitudinal changes.

This study estimated the genetic and environmental determinants of plasma leptin and insulin levels and of obesity-related phenotypes. Included in this analysis were family members from 80 families living in kibbutz settlements, who participated in two examinations 8-10 years apart. We estimated that polygenes explained 30-50% of the adjusted leptin and insulin levels and 30-70% of the anthropometric phenotypes. This study demonstrated a significant genetic influence on longitudinal changes in leptin and BMI (h(2) = 0.45) and small-to-moderate heritability estimates for changes in insulin and other obesity-related phenotypes. In bivariate genetic analyses, we observed positive genetic correlations between leptin and anthropometric phenotypes, suggesting that shared effects of the same sets of loci account for 20-30% of the additive genetic variance in these pairs of variables. Shared genetic factors also account for 20-25% of the additive genetic variance in insulin-anthropometric pairs of variables.

Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas.

Tenascin-C (TNC) expression is known to correlate with malignancy in glioblastoma (GBM), a highly invasive and aggressive brain tumor that shows limited response to conventional therapies. In these malignant gliomas as well as in GBM cell lines, we found Notch2 protein to be strongly expressed. In a GBM tumor tissue microarray, RBPJk protein, a Notch2 cofactor for transcription, was found to be significantly coexpressed with TNC. We show that the TNC gene is transactivated by Notch2 in an RBPJk-dependent manner mediated by an RBPJk binding element in the TNC promoter. The transactivation is abrogated by a Notch2 mutation, which we detected in the glioma cell line Hs683 that does not express TNC. This L1711M mutation resides in the RAM domain, the site of interaction between Notch2 and RBPJk. In addition, transfection of constructs encoding activated Notch2 or Notch1 increased endogenous TNC expression identifying TNC as a novel Notch target gene. Overexpression of a dominant negative form of the transcriptional coactivator MAML1 or knocking down RBPJk in LN319 cells led to a dramatic decrease in TNC protein levels accompanied by a significant reduction of cell migration. Because addition of purified TNC stimulated glioma cell migration, this represents a mechanism for the invasive properties of glioma cells controlled by Notch signaling and defines a novel oncogenic pathway in gliomagenesis that may be targeted for therapeutic intervention in GBM patients.

Clinical course of neuropathologically confirmed frontal-variant Alzheimer's disease.

Background A 66-year-old man presented with a 3-year history of personality changes marked by increasing apathy, social withdrawal and deficits in complex attention, and a 1-year history of progressive memory problems and difficulties in planning and carrying out complex tasks. Investigations Three neuropsychological examinations over 2 years, neurological examination, routine laboratory tests, brain MRI, single-photon emission CT scan, genetic analyses, and neuropathological examination. Diagnosis A clinical diagnosis of frontal-variant frontotemporal dementia was superseded by postmortem neuropathological evidence, which established a diagnosis of frontal-variant Alzheimer's disease. Management The patient and his spouse were referred for counseling, and the patient was referred for follow-up examinations.

Loss of NOTCH2 positively predicts survival in subgroups of human glial brain tumors.

The structural complexity of chromosome 1p centromeric region has been an obstacle for fine mapping of tumor suppressor genes in this area. Loss of heterozygosity (LOH) on chromosome 1p is associated with the longer survival of oligodendroglioma (OD) patients. To test the clinical relevance of 1p loss in glioblastomas (GBM) patients and identifiy the underlying tumor suppressor locus, we constructed a somatic deletion map on chromosome 1p in 26 OG and 118 GBM. Deletion hotspots at 4 microsatellite markers located at 1p36.3, 1p36.1, 1p22 and 1p11 defined 10 distinct haplotypes that were related to patient survival. We found that loss of 1p centromeric marker D1S2696 within NOTCH2 intron 12 was associated with favorable prognosis in OD (P = 0.0007) as well as in GBM (P = 0.0175), while 19q loss, concomitant with 1p LOH in OD, had no influence on GBM survival (P = 0.918). Assessment of the intra-chromosomal ratio between NOTCH2 and its 1q21 pericentric duplication N2N (N2/N2N-test) allowed delineation of a consistent centromeric breakpoint in OD that also contained a minimally lost area in GBM. OD and GBM showed distinct deletion patterns that converged to the NOTCH2 gene in both glioma subtypes. Moreover, the N2/N2N-test disclosed homozygous deletions of NOTCH2 in primary OD. The N2/N2N test distinguished OD from GBM with a specificity of 100% and a sensitivity of 97%. Combined assessment of NOTCH2 genetic markers D1S2696 and N2/N2N predicted 24-month survival with an accuracy (0.925) that is equivalent to histological classification combined with the D1S2696 status (0.954) and higher than current genetic evaluation by 1p/19q LOH (0.762). Our data propose NOTCH2 as a powerful new molecular test to detect prognostically favorable gliomas.

Statins induce differentiation and cell death in neurons and astroglia.

Statins are potent inhibitors of the hydroxy-methyl-glutaryl-coenzyme A reductase, the rate limiting enzyme for cholesterol biosynthesis. Experimental and clinical studies with statins suggest that they have beneficial effects on neurodegenerative disorders. Thus, it was of interest to characterize the direct effects of statins on CNS neurons and glial cells. We have treated defined cultures of neurons and astrocytes of newborn rats with two lipophilic statins, atorvastatin and simvastatin, and analyzed their effects on morphology and survival. Treatment of astrocytes with statins induced a time- and dose-dependent stellation, followed by apoptosis. Similarly, statins elicited programmed cell death of cerebellar granule neurons but with a higher sensitivity. Analysis of different signaling cascades revealed that statins fail to influence classical pathways such as Akt or MAP kinases, known to be activated in CNS cells. In addition, astrocyte stellation triggered by statins resembled dibutryl-cyclic AMP (db-cAMP) induced morphological differentiation. However, in contrast to db-cAMP, statins induced upregulation of low-density lipoprotein receptors, without affecting GFAP expression, indicating separate underlying mechanisms. Analysis of the cholesterol biosynthetic pathway revealed that lack of mevalonate and of its downstream metabolites, mainly geranylgeranyl-pyrophosphate (GGPP), is responsible for the statin-induced apoptosis of neurons and astrocytes. Moreover, astrocytic stellation triggered by statins was inhibited by mevalonate and GGPP. Interestingly, neuronal cell death was significantly reduced in astrocyte/neuron co-cultures treated with statins. We postulate that under these conditions signals provided by astrocytes, e.g., isoprenoids play a key role in neuronal survival.

Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes.

The atherogenic lipoprotein phenotype is characterized by an increase in plasma triglycerides, a decrease in high-density lipoprotein (HDL), and the prevalence of small, dense low-density lipoprotein (LDL) particles. The present study investigated the clinical significance of LDL size and subclasses as markers of atherosclerosis in diabetes type 2. Thirty-eight patients with type 2 diabetes, total cholesterol of less than 6.5 mmol/L, and hemoglobin A1c (HbA1c) of less than 9% were studied. Median age was 61 years, mean (+/-SD) body mass index 29 +/- 4.3 kg/m2 , and mean HbA1c 7.1 +/- 0.9 %. Laboratory parameters included plasma lipids and lipoproteins, lipoprotein (a), apolipoprotein (apo) A-I, apo B-100, apo C-III, and high-sensitivity C-reactive protein. Low-density lipoprotein size and subclasses were measured by gradient gel electrophoresis and carotideal intima media thickness (IMT) by duplex ultrasound. By factor analysis, 10 out of 21 risk parameters were selected: age, body mass index, systolic blood pressure, smoking (in pack-years), HbA1c, high-sensitivity C-reactive protein, lipoprotein (a), LDL cholesterol, HDL cholesterol, and LDL particle size. Multivariate analysis of variance of these 10 risk parameters identified LDL particle size as the best risk predictor for the presence of coronary heart disease (P = .002). Smaller LDL particle size was associated with an increase in IMT (P = .03; cut-off >1 mm). Within the different lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apo B, apo A-I, apo C-III, LDL particle size), LDL particle size was most strongly associated with the presence of coronary heart disease (P = .002) and IMT (P = .03). It is concluded that LDL size is the strongest marker for clinically apparent as well as non-apparent atherosclerosis in diabetes type 2.

Large heterogeneity of mutations in the gene encoding the low-density lipoprotein receptor in subjects with familial hypercholesterolaemia.

Molecular genetic testing for presymptomatic identification of subjects affected by familial hypercholesterolaemia (FH) is difficult due to the heterogeneity of the mutations in the gene encoding the low-density lipoprotein receptor (LDLR) in most populations. This investigation presents a detailed analysis of comparable, country-specific prevalence data of LDLR mutations in subjects with clinically defined FH and assesses the heterogeneous mutation diversity observed in most geographic regions.

Argyrophilic grain disease: molecular genetic difference to other four-repeat tauopathies.

Argyrophilic grain disease (AgD) is a four-repeat tauopathy that is almost exclusively restricted to allocortical areas. Progressive supranuclear palsy and corticobasal degeneration also show predominant deposition of four-repeat tau filaments, and are associated with the tau H1 haplotype. We investigated a possible association between AgD and the tau H1 haplotype. In AgD, no difference between the prevalence of the tau H1 haplotype or H1/H1 genotype was observed when compared to non-demented control cases. These data suggest that a dysfunction of the tau protein in AgD-in contrast to other four-repeat tauopathies-may arise irrespective of the genetic background regarding the tau H1 or H2 haplotypes.

Indinavir inhibits sterol-regulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations.

BACKGROUND: A syndrome characterized by hypertriglyceridaemia, hypercholesterolaemia, hyperinsulinaemia, and lipodystrophy has been found to be associated with highly active antiretroviral treatment (HAART) including protease inhibitors. A marker predicting this syndrome has been previously identified in the gene encoding the sterol-regulatory element-binding protein (SREBP)-1c, a regulator of triglycerides, cholesterol, insulin, and adipocytes. OBJECTIVE: A possible inhibition of SREBP-1c-dependent genes by the protease inhibitor indinavir and its possible reversal by the lipid-lowering drug simvastatin were studied. METHODS: The effects of indinavir and simvastatin on the inhibition/activation of SREBP-1c-dependent genes were compared with the effects of indinavir and simvastatin on the inhibition/activation of SREBP-1c-independent genes. RESULTS: Indinavir inhibited the SREBP-1c-dependent genes encoding the lipoprotein lipase (103 nmol/l resulted in an inhibition of 12.4%; P = 0.0051) and the fatty acid synthase (103 nmol/l resulted in an inhibition of 30.3%; P = 0.036) in a dose-dependent fashion but not the SREBP-1c-independent gene encoding the low-density lipoprotein receptor. Simvastatin antagonized the indinavir-induced SREBP-1c-inhibition. CONCLUSIONS: Indinavir inhibits important effector genes of the SREBP-1c pathway, explaining major HAART-related adverse effects.

Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia.

Sterol-regulatory element-binding protein (SREBP)-2 is a key regulator of cholesterol. When cells are deprived of cholesterol, proteolytic cleavage releases the NH(2)-terminal domain of SREBP-2 that binds and activates the promoters of SREBP-2-regulated genes including the genes encoding the low-density lipoprotein (LDL) receptor, 3-hydroxymethyl-3-glutaryl-(HMG-)CoA-synthase, and HMG-CoA-reductase. Thus, SREPB-2 gene activation leads to enhanced cholesterol uptake and biosynthesis. A novel protein polymorphism (SREBP-2-595A/G) discovered in the regulatory domain of human SREBP-2 was investigated regarding its impact on cholesterol homeostasis. In human embryonic kidney (HEK)-293-cells, the cleavage-rate of the SREBP-2-595A-isoform was slightly decreased compared to that of the SREBP-2-595G-isoform. Since cleavage of SREBP-2 activates the LDL receptor-mediated uptake of plasma cholesterol, we hypothesized the LDL receptor-mediated uptake to be decreased in homozygous SREBP-2-595A-carriers and thus, plasma total cholesterol (TC) to be higher than in SREBP-2-595G-carriers. Multiple linear regression analysis of population samples from Switzerland (N=1334) and Israel (N=923) demonstrated a significant positive, gene dose-dependent association of the SREBP-2-595A-isoform with higher plasma TC (P=0.001). This cholesterol-modulating effect was present in hypercholesterolaemic (DeltaTC=1.05 mmol/l, 14.4%; P=0.002; N=477), but absent in normocholesterolaemic subjects (DeltaTC=0.06 mmol/l, 1.4%; P=0.334; N=1780). In summary, a slightly but constantly decreased cleavage-rate of the SREBP-2-595A-isoform compared to that of the SREBP-2-595G-isoform may lead to a reduced transcriptional activation of the LDL receptor-gene weakening the SREBP-mediated compensation mechanisms, and may, therefore, be a critical factor in the development of polygenic hypercholesterolaemia.