Search

Elevated 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.We 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.It 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.For 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).

Lipoprotein(a) has long been regarded as a risk factor for cardiovascular disease; however, its routine use in clinical practice has been hampered by difficulties inherent in the measurement of this complex lipoprotein. The major challenges relate to its size heterogeneity and related issues including (1) use of appropriate calibrators (2) standardization of calibration protocols (3) traceability and (4) reporting units. In the UK, results from the current EQA schemes for lipoprotein(a) suggest that there is considerable work required to standardize lipoprotein(a) measurement. This is becoming increasingly pertinent with the increasing recognition of lipoprotein(a) as an independent risk factor for cardiovascular disease in international guidelines and the emergence of novel antisense therapies to effectively reduce lipoprotein(a). This article raises awareness of the importance of measurement of lipoprotein(a) for the assessment of cardiovascular disease risk and gives guidance to clinical laboratories regarding choice of appropriate assays.

Summary Aims The aims of this study were to determine the diagnostic yield of a dedicated heart failure diagnosis clinic and the impact of using different guideline recommended N-terminal pro B-type natriuretic peptide (NT-proBNP) referral thresholds on diagnosis and referral patterns. Methods and results Patients referred by primary care between September 2011 and May 2013 were included in the analysis. Data collected included baseline characteristics, NT-proBNP levels, echocardiographic and clinical findings, final diagnosis and outcome. The impact of using Newcastle (locally modified age-adjusted NT-proBNP thresholds), National Institute for Health and Care Excellence (NICE) and European Society of Cardiology (ESC) NT-proBNP thresholds on diagnosis and referrals was determined by applying the different guidelines to this population. A total of 208 patients were referred; median age 77.5 years and 62.5% were women. Thirty-four patients (16.3%) had systolic heart failure, 50 patients (24.0%) had heart failure with preserved ejection fraction. One hundred and six patients (51.0%) did not have heart failure. Using NICE guidelines (NT-proBNP ≥ 400 ng/l) instead of the Newcastle age-adjusted NT-proBNP referral thresholds results in 59 fewer referrals, but eight heart failure diagnoses were missed. Using the ESC cut-off of NT-proBNP ≥ 125 ng/l would result in 88 additional referrals; one diagnosis of heart failure would be missed. Over a mean follow-up of 16.8 ± 6 months there were 21 deaths and 47 hospital admissions. Conclusion The Newcastle age-adjusted thresholds led to more referrals in comparison to NICE guidelines but are more sensitive in diagnosing heart failure. Using ESC recommended thresholds results in a similar diagnostic yield to our age-adjusted thresholds, but has the potential to significantly increase the referrals in patients ≥ 75 years, which may result in a lower diagnostic yield.

Serum total testosterone (tT)9 includes both free testosterone (fT) (0.5%–3% of total and believed to be the biologically active form) and sex hormone–binding globulin (SHBG)- and albumin-bound forms (1). Guidelines for diagnosing and treating male hypogonadism that emphasize measurement of tT (2) may not address the major variations in SHBG and consequent testosterone bioavailability (testosterone bioavailability [BT] either calculated or assayed directly) that are associated with age, obesity, anticonvulsant therapy, and thyroid and liver disease. For these reasons, recent Endocrine Society of Australia guidelines (3) acknowledge the value of measuring SHBG as well as BT, but nevertheless state that, “There is no evidence that free or bioavailable testosterone levels, which are usually not directly measured but calculated…are a better measure of androgen status than total testosterone level. Moreover, reference intervals for these [BT levels] are even less well defined than those for measured testosterone concentrations. Therefore, they [BT levels] are not recommended for clinical decision-making.” Although commercially available direct fT assays are not always robust, calculated fT (c-fT) values from a mass-action …

This review describes pathophysiology of post-surgical hypophosphatemia (HP), which has particularly high incidence following liver transplantation. HP remains poorly understood; and there is a lack of universally accepted guidelines for its investigation and management. The pathogenesis of HP following major liver surgery has been hypothesized as being due either to excessive utilization by regenerating liver or increased urinary losses of phosphate. This review provides evidence that excessive urinary loss rather than increased Pi uptake by the liver is the most likely mechanism, and this may be mediated by recently described phosphaturic factors, known as phosphatonins. Until recently blood Pi homeostasis had been explained solely in terms of classical hormones, i.e., vitamin D and PTH. It is however increasingly recognized that phosphatonins may play a critical role in the post-operative HP, but the exact mechanism and candidate phosphaturic factor has not yet been identified. In this review, we have described likely mechanisms and suggest candidate phosphatonins that may mediate urinary Pi loss following liver transplantation. We also discuss the biochemical consequences of cellular Pi depletion, which exposes some gaps in the utilization of established knowledge and therefore in the management of HP. The main aspects of pathophysiology of HP and cellular Pi depletion are presented to provide rational for novel biochemical investigations, which are likely to improve monitoring of HP associated metabolic stress as well as extent of severity of HP, and thereby enhance management of these patients.

Background —We examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study. Methods and Results —Our definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of ≥7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of ≥7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort. Conclusions —We concluded that the assignment to pravastatin therapy resulted in a 30% reduction ( P =0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.

Introduction The ICON1 study (a study to Improve Cardiovascular Outcomes in high-risk older patieNts with acute coronary syndrome) is a prospective observational study of older patients (≥75 years old) with non-ST-elevation acute coronary syndrome managed by contemporary treatment (pharmacological and invasive). The aim of the study was to determine the predictors of poor cardiovascular outcomes in this age group and to generate a risk prediction tool. Methods and analysis Participants are recruited from 2 tertiary hospitals in the UK. Baseline evaluation includes frailty, comorbidity, cognition and quality-of-life measures, inflammatory status assessed by a biomarker panel, including microRNAs, senescence assessed by telomere length and telomerase activity, cardiovascular status assessed by arterial stiffness, endothelial function, carotid intima media thickness and left ventricular systolic and diastolic function, and coronary plaque assessed by virtual histology intravascular ultrasound and optical coherence tomography. The patients are followed-up at 30 days and at 1 year for primary outcome measures of death, myocardial infarction, stroke, unplanned revascularisation, bleeding and rehospitalisation. Ethics and dissemination The study has been approved by the regional ethics committee (REC 12/NE/016). Findings of the study will be presented in scientific sessions and will be published in peer-reviewed journals. Trial registration number NCT01933581: Pre-results.

Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, lack of efficacy and adverse effects mean that a substantial proportion of patients fail to achieve acceptable LDL-C levels with currently available lipid-lowering drugs. Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic strategy to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the receptor for lysosomal degradation. The recognition that inhibition of PCSK9 increases LDL receptor activity has led to the development of a number of approaches to directly target PCSK9. Numerous monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials, involving various patient categories on different background lipid-lowering therapies. Current evidence shows reductions in LDL-C levels of up to 70 % may be achieved with PCSK9 inhibition, independent of background statin therapy. This review examines the most recent evidence and future prospects for the use of PCSK9 inhibitors in the prevention of cardiovascular disease.

The six different HCV-genotypes have marked differences in response to therapy with pegylated interferon-α and ribavirin. The introduction of the direct acting antiviral (DAA) protease inhibitors, telaprevir and boceprevir in combination with pegylated interferon-α and ribavirin has become the new standard of care for genotype 1 infection. Several host factors associated with response to pegylated interferon-α and ribavirin are not as important in predicting response to triple therapy, and yet low-density lipoprotein cholesterol (LDLC) and statin use remain important associations of outcome with DAAs. This review focuses on the clinical associations between lipids and treatment response to interferon based antiviral treatments. We consider how understanding the interactions of HCV and host lipid metabolism remains relevant in the era of DAAs for genotype 1 infection and for treatment of non-genotype 1 chronic hepatitis C.

The physical association of hepatitis C virus (HCV) particles with lipoproteins in plasma results in distribution of HCV in a broad range of buoyant densities. This association is thought to increase virion infectivity by mediating cell entry via lipoprotein receptors. We sought to determine if factors that affect triglyceride-rich lipoprotein (TRL) metabolism alter the density and dynamics of HCV particles in the plasma of patients with chronic HCV infection.Fasting patients (n = 10) consumed a high-fat milkshake; plasma was collected and fractionated by density gradients. HCV- RNA was measured in the very-low-density fraction (VLDF, d1.025 g/mL) before and at 7 serial time points postprandially.The amount of HCV RNA in the VLDF (HCV(VLDF)) increased a mean of 26-fold, peaking 180 minutes after the meal (P.01). Quantification of HCV RNA throughout the density gradient fractions revealed that HCV(VLDF) rapidly disappeared, rather than migrating into the adjacent density fraction. Immuno-affinity separation of the VLDF, using antibodies that recognize apolipoprotein B-100 and not apolipoprotein B-48, showed that HCV(VLDF) is composed of chylomicron- and VLDL-associated HCV particles; peaking 120 and 180 minutes after the meal, respectively. Plasma from fasting HCV-infected patients mixed with uninfected plasma increased the quantity of HCV(VLDF), compared with that mixed with phosphate-buffered saline, showing extracellular assembly of HCV(VLDF).Dietary triglyceride alters the density and dynamics of HCV in plasma. The rapid clearance rate of HCV(VLDF) indicates that association with TRL is important for HCV infectivity. HCV particles, such as exchangeable apolipoproteins, appear to reassociate with TRLs in the vascular compartment.

Background: We measured plasma PCSK9 concentrations in healthy men with a PCSK9 (proprotein convertase subtilisin/kexin type 9) loss-of-function variant (p.R46L), in statin-treated patients with a clinical diagnosis of familial hypercholesterolemia (FH) and carrying a PCSK9 gain-of-function mutation (p.D374Y), and in statin-treated patients with FH due to different genetic causes. Methods: PCSK9 was measured with a previously described ELISA. Results: In 81 healthy middle-aged Caucasian men, the PCSK9 concentration was significantly associated with the concentrations of total cholesterol (r = 0.42; P < 0.0001), LDL cholesterol (r = 0.34; P = 0.01), and triglycerides (r = 0.25; P = 0.02). In p.R46L carriers, mean (SD) concentrations of PCSK9 were 15% lower than in RR individuals [65.5 μg/L (21.6 μg/L) vs 77.5 μg/L (18.2 μg/L); P = 0.03]. In patients with the p.D374Y variant (n = 7), the mean PCSK9 concentration was significantly lower than in the combined group of patients with an LDLR (low density lipoprotein receptor) mutation (n = 25), an APOB [apolipoprotein B (including Ag(x) antigen)] variant encoding p.R3527Q (n = 6), or no detectable mutation (n = 14) [96.4 μg/L (42.5 μg/L) vs 151.6 μg/L (69.6 μg/L); P = 0.02]. Two of the 14 patients with no mutation had PCSK9 concentrations below the mean for p.D374Y carriers; sequencing of the PCSK9 gene and promoter revealed no mutations. Among 409 FH patients, we identified 6 carriers of the promoter variant −287G>A (1.5%), a frequency similar to that (1.0%) previously reported for 2772 healthy men in the UK. In neither group was the −287G>A variant associated with differences in lipid traits. Conclusions: The loss-of-function p.R46L variant is associated with the expected lower concentrations of circulating PCSK9; the gain-of-function p.D374Y mutation is also associated with lower concentrations, presumably because of the higher affinity of this variant for the LDL receptor and its more rapid clearance. In treated FH patients, a low plasma PCSK9 concentration does not appear to be a useful screening tool for identifying novel PCSK9 mutations.

Background Targets for cholesterol reduction are part of the Quality Outcomes Framework and general practitioners have to meet these targets to fulfil their remuneration package. By contrast, there are no targets for the accuracy of cholesterol or other lipid measurements and no recent surveys on performance of these assays. We have assessed the performance of lipid measurement of the available methods in the UK. Methods Serum samples collected from individual donors attending the national blood service were distributed after values were obtained from a secondary reference laboratory. Samples were sent to participant laboratories to assess different methods' analytical performance on single donation specimens, on routine external quality assessment pooled specimens, on specimens subjected to a range of freeze–thaw cycles and on frozen-stored specimens. Results Differences in measured cholesterol were found that were method-dependent and related to triglyceride content. HDL-cholesterol (HDL-C) showed significant positive bias in all assays. Individual donor specimens showed no significant changes with differing numbers of freeze–thaw cycles. Pooled serum was stable for up to six months. Conclusions Most cholesterol measurements are accurate but some methods are affected by triglyceride interference. HDL-C methods show significant positive bias. Although there are potential matrix effects introduced as a result of specimen preparation, additional work is needed to show if these effects are present in fresh patient samples.

Familial hypercholesterolemia (FH) is a common single gene disorder, which predisposes to coronary artery disease. In a previous study, we have shown that in patients with definite FH around 20% had no identifiable gene defect after screening the entire exon coding area of the low density lipoprotein receptor (LDLR) and testing for the common Apolipoprotein B (ApoB) R3500Q mutation. In this study, we have extended the screen to additional families and have included the non-coding intron splice regions of the gene. In families with definite FH (tendon xanthoma present, n=68) the improved genetic screening protocol increased the detection rate of mutations to 87%. This high detection rate greatly enhances the potential value of this test as part of a clinical screening program for FH. In contrast, the use of a limited screen in patients with possible FH (n=130) resulted in a detection rate of 26%, but this is still of significant benefit in diagnosis of this genetic condition. We have also shown that 14% of LDLR defects are due to splice site mutations and that the most frequent splice mutation in our series (c.1845+11 c>g) is expressed at the RNA level. In addition, DNA samples from the patients in whom no LDLR or ApoB gene mutations were found, were sequenced for the NARC-1 gene. No mutations were identified which suggests that the role of NARC-1 in causing FH is minor. In a small proportion of families (

Atherosclerosis has been described as a liver disease of the heart [1]. The liver is the central regulatory organ of lipid pathways but since dyslipidaemias are major contributors to cardiovascular disease and type 2 diabetes rather than liver disease, research in this area has not been a major focus for hepatologists. Virus-host interaction is a continuous co-evolutionary process [2] involving the host immune system and viral escape mechanisms [3]. One of the strategies HCV has adopted to escape immune clearance and establish persistent infection is to make use of hepatic lipid pathways. This review aims to: • update the hepatologist on lipid metabolism • review the evidence that HCV exploits hepatic lipid pathways to its advantage • discuss approaches to targeting host lipid pathways as adjunctive therapy.