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BackgroundLysosomal acid lipase deficiency (LALD) is a rare autosomal recessive metabolic disorder. Mutations in the LIPA gene that encodes LAL result in disrupted triglyceride metabolism. Presentations and severity of the disorder are diverse and are often non-specific. Characterisations of LALD include dyslipidaemia and abnormal liver function which can overlap with conditions such as familial hypercholesterolaemia and non-alcoholic fatty liver disease (NAFLD). The rarity of LALD may mean that the condition is unrecognised or misdiagnosed. The development of effective enzyme replacement therapy for LALD has provided motivation for identifying the condition clinically. Diagnosis of LALD by genetic testing is costly. However the relatively inexpensive assay of LAL activity in dried blood spot (DBS) has made the diagnosis of LALD in clinical practice more available. We studied LALD screening in 3 cohorts: patients from hospital Lipid and Diabetes Clinics selected using the current recommended criteria,1 patients from hospital Liver Clinic who either had histological features in their liver biopsies that were consistent with LALD or who had diagnoses of non-alcoholic steatohepatitis (NASH), NAFLD or cryptogenic cirrhosis, and genetic testing for patients found to have reduced LAL activity to detect LALD carriers.MethodEligible patients were consented for LALD screening. A single sample of blood was obtained either from a finger prick or from a venous blood sample. The blood was transferred to a DBS filter paper for processing. LAL activity Results1730 patients were screened for LALD from 8 centres in the UK. None of the patients in the cohort tested positive for LALD. 27 patients consented to have genetic testing. No abnormalities were detected. 100 patients in the Liver cohort were screened for LALD and none was positive for LALD.ConclusionUsing the eligibility criteria we adopted, the detection rate of LALD was meagre. In our cohorts, we did not identify any patient with undiagnosed LALD in hospital Lipid, Diabetes or Liver clinics.

BACKGROUND: There is a lack of information on the health care of familial hypercholesterolemia (FH).OBJECTIVE: The objective of this study was to compare the health care of FH in countries of the Asia-Pacific region and Southern Hemisphere.METHODS: A series of questionnaires were completed by key opinion leaders from selected specialist centers in 12 countries concerning aspects of the care of FH, including screening, diagnosis, risk assessment, treatment, teaching/training, and research; the United Kingdom (UK) was used as the international benchmark.RESULTS: The estimated percentage of patients diagnosed with the condition was low (overall

Background Enzyme replacement therapy (ERT) with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is being developed to treat patients with ASM deficiency (ASMD), commonly known as Niemann–Pick disease (NPD) types A or B. This study assessed the effect of ERT on lipid parameters and inflammatory markers. Methods Serum and plasma samples from five adults with NPD type B (NPD-B) who received olipudase alfa ERT for 26 weeks were analysed. We also collected fasting blood samples from fifteen age- and sex-matched participants as reference and comparison group. We measured fasting lipid profile, apolipoproteins B48 and B100 (apoB48 and apoB100), apolipoprotein A1 (apoA1), proprotein convertase subtilisin/klexin type 9 (PCSK9) mass, oxidised low-density lipoprotein (oxLDL), small dense low-density lipoprotein cholesterol (sdLDL-C) and tumour necrosis factor α (TNF-α). Results Patients with NPD-B, compared with age and sex matched reference group, had higher triglycerides, PCSK9, apoB48, oxLDL and TNF-α and lower high density lipoprotein cholesterol (HDL-C) and apoA1. Treatment with ERT was associated with improved lipid parameters including total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C), sdLDL-C, oxLDL and apoB100. Though there was an increase in apoA1, HDL-C was slightly reduced. TNF-α showed a reduction. ApoB100 decreased in parallel with a decrease in total serum PCSK9 mass after ERT. Conclusion This study demonstrated that patients with NPD-B had a proatherogenic lipid profile and higher circulating TNF-α compared to reference group. There was an improvement in dyslipidaemia after olipudase alfa. It was possible that reductions in LDL-C and apoB100 were driven by reductions in TNF-α and PCSK9 following ERT.

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

Summary Obesity is an emerging independent risk factor for susceptibility to and severity of coronavirus disease 2019 (COVID‐19) caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). Previous viral pandemics have shown that obesity, particularly severe obesity (BMI > 40 kg/m2), is associated with increased risk of hospitalization, critical care admission and fatalities. In this narrative review, we examine emerging evidence of the influence of obesity on COVID‐19, the challenges to clinical management from pulmonary, endocrine and immune dysfunctions in individuals with obesity and identify potential areas for further research. We recommend that people with severe obesity be deemed a vulnerable group for COVID‐19; clinical trials of pharmacotherapeutics, immunotherapies and vaccination should prioritize inclusion of people with obesity.

Hypercholesterolaemia is amongst the most common conditions encountered in the medical profession. It remains one of the key modifiable cardiovascular risk factors and there have been recent advances in the risk stratification methods and treatment options available. In this review, we provide a background into hypercholesterolaemia for non-specialists and consider the merits of the different risk assessment tools available. We also provide detailed considerations as to: i) when to start treatment, ii) what targets to aim for and iii) the role of low density lipoprotein cholesterol.

Category: Basic Sciences/Biologics, Hindfoot, Sports Introduction/Purpose: Heel pain syndrome is a complex condition causing morbidity and decreases the quality of life in our adult population. It is known that individuals with a body mass index (BMI) of more than >30 kg/m2 have increased risk of plantar fasciitis. However, heel pain consists of larger entities not merely to plantar fasciitis alone. Limited study mentioned the association between hypertension and musculoskeletal pain. Platelet rich plasma (PRP) therapy is an emerging treatment option for its regenerative properties in the treatment of degenerative enthesopathic conditions as in plantar fasciitis and lateral elbow epicondylitis. We hypothesize that obesity (BMI>30 kg/m2) and hypertension do influence the poorer outcome after PRP injection in individuals with heel pain. Methods: We analysed 154 heel pain cases from orthopaedic outpatient clinic that were treated with PRP injection. BMI and BP were taken as preadmission measurements with at least three readings for blood pressure. PRP was harvested from the antecubital vein, and spun in a centrifuge machine. Follow-up was conducted with AOFAS Ankle Hindfoot system before injection, 6 weeks and up to 2 years after injection. Results: Mean age was 49.96 (range 20-81 years old) with 52.60% female and 47.4% male. Plantar fasciitis was the majority source of heel pain (71.43%) followed by achilles tendinopathy (26.62%), posterior tibial tendon disorder (1.3%), and peroneal tendinopathy (0.65%). One hundred and twenty-eight (83.1%) patients achieved resolution of heel pain and related symptoms after injection. Statistical analysis was performed using one sample student t-test. No statistical significant result was found in both overweight (p =0.29) and obesity grade 1 (p = 0.40). Statistical significant result found in the prehypertension group (pConclusion: Based on this preliminary data, we recommend weight loss with trials of lifestyle modification in individuals with obesity, and better control of our patients’ blood pressure in order to achieve comparable outcome with normal BMI population.

Rationale: Familial Hypercholesterolemia (FH) is a genetic condition that predisposes patients to substantially increased risk of early-onset atherosclerotic cardiovascular disease. FH risks can be minimized through regular participation in three self-management behaviors: physical activity, healthy eating, and taking cholesterol lowering medication.Objective: The present study tested the effectiveness of an integrated social cognition model in predicting intention to participate in the self-management behaviors in FH patients from seven countries.Method: Consecutive patients in FH clinics from Australia, Hong Kong, Brazil, Malaysia, Taiwan, China, and UK (total N = 726) completed measures of social cognitive beliefs about illness from the common sense model of self-regulation, beliefs about behaviors from the theory of planned behavior, and past behavior for the three self-management behaviors.Results: Structural equation models indicated that beliefs about behaviors from the theory of planned behavior, namely, attitudes, subjective norms, and perceived behavioral control, were consistent predictors of intention across samples and behaviors. By comparison, effects of beliefs about illness from the common sense model were smaller and trivial in size. Beliefs partially mediated past behavior effects on intention, although indirect effects of past behavior on intention were larger for physical activity relative to taking medication and healthy eating. Model constructs did not fully account for past behavior effects on intentions. Variability in the strength of the beliefs about behaviors was observed across samples and behaviors.Conclusion: Current findings outline the importance of beliefs about behaviors as predictors of FH self-management behaviors. Variability in the relative contribution of the beliefs across samples and behaviors highlights the imperative of identifying sample- and behavior-specific correlates of FH self-management behaviors.

Background and aims Untreated individuals with familial hypercholesterolaemia (FH) are at increased risk of developing premature cardiovascular disease (CVD). Early diagnosis and treatment can result in a normal life expectancy. A recent survey commissioned by the European Atherosclerosis Society (EAS) reported a lack of awareness of FH in the general population. We conducted a survey to assess knowledge among healthcare professionals involved in the assessment and management of cardiovascular risk and disease in the United Kingdom. Methods A survey designed to assess knowledge of diagnostic criteria, risk assessment, the role of cascade screening, and management options for patients with FH was distributed to 1000 healthcare professionals (response rate 44.3%). The same survey was redistributed following attendance at an educational session on FH. Results 151 respondents (40.5%) reported having patients under their care who would meet the diagnostic criteria for FH, but just 61.4% recognized that cardiovascular risk estimation tools cannot be applied in FH, and only 22.3% understood the relative risk of premature CVD compared to the general population. Similarly, just 65.9% were aware of recommendations regarding cascade screening. Conclusions The prevalence and associated risk of FH continue to be underestimated, and knowledge of diagnostic criteria and treatment options is suboptimal. These results support the recent Consensus Statement of the EAS and production of quality standards by the National Institute for Health and Care Excellence. Further work is required to formulate interventions to improve FH awareness and knowledge, and to determine the effect these interventions have on patient outcomes.

Rationale Familial Hypercholesterolemia (FH) is a genetic condition that predisposes patients to substantially increased risk of early-onset atherosclerotic cardiovascular disease. FH risks can be minimized through regular participation in three self-management. Behaviors physical activity, healthy eating, and taking cholesterol lowering medication. Objective The present study tested the effectiveness of an integrated social cognition model in predicting intention to participate in the self-management behaviors in FH patients from seven countries. Method Consecutive patients in FH clinics from Australia, Hong Kong, Brazil, Malaysia, Taiwan, China, and UK (total N = 726) completed measures of social cognitive beliefs about illness from the common sense model of self-regulation, beliefs about behaviors from the theory of planned behavior, and past behavior for the three self-management behaviors. Results Structural equation models indicated that beliefs about behaviors from the theory of planned behavior, namely, attitudes, subjective norms, and perceived behavioral control, were consistent predictors of intention across samples and behaviors. By comparison, effects of beliefs about illness from the common sense model were smaller and trivial in size. Beliefs partially mediated past behavior effects on intention, although indirect effects of past behavior on intention were larger for physical activity relative to taking medication and healthy eating. Model constructs did not fully account for past behavior effects on intentions. Variability in the strength of the beliefs about behaviors was observed across samples and behaviors. Conclusion Current findings outline the importance of beliefs about behaviors as predictors of FH self-management behaviors. Variability in the relative contribution of the beliefs across samples and behaviors highlights the imperative of identifying sample- and behavior-specific correlates of FH self-management behaviors.

Background High rates of inadequate health literacy are associated with maladaptive health outcomes in chronic disease including increased mortality and morbidity rates, poor treatment adherence and poor health. Adequate health literacy may be an important factor in the effective treatment and management of familial hypercholesterolemia, and may also be implicated in genetic screening for familial hypercholesterolemia among index cases. The present study examined the prevalence and predictors of health literacy in familial hypercholesterolemia patients attending clinics in seven countries. Design Cross-sectional survey. Methods Consecutive FH patients attending clinics in Australia, Brazil, China, Hong Kong, Malaysia, Taiwan and the UK completed measures of demographic variables (age, gender, household income and highest education level) and a brief three-item health literacy scale. Results Rates of inadequate health literacy were lowest in the UK (7.0%), Australia (10.0%), Hong Kong (15.7%) and Taiwan (18.0%) samples, with higher rates in the Brazil (22.0%), Malaysia (25.0%) and China (37.0%) samples. Income was an independent predictor of health literacy levels, accounting for effects of age. Health literacy was also independently related to China national group membership. Conclusions Findings indicate non-trivial levels of inadequate health literacy in samples of familial hypercholesterolemia patients. Consistent with previous research in chronic illness, inadequate health literacy is related to income as an index of health disparities. Chinese familial hypercholesterolemia patients are more likely to have high rates of inadequate health literacy independent of income. Current findings highlight the imperative of education interventions targeting familial hypercholesterolemia patients with inadequate health literacy.

Although familial hypercholesterolemia (FH) can be effectively managed using cholesterol-lowering medication, patients often fall short of complete treatment adherence. Identifying the psychological factors associated with self-regulation of FH medication is important to inform interventions to maximize adherence. The aim of the present study was to test an integrated psychological model in predicting FH patients' intentions to take medication.FH patients attending clinics in seven countries were invited to participate in a cross-sectional survey study. Consenting patients (N = 551) completed self-report measures of generalized beliefs about medication overuse and harms, beliefs in treatment effectiveness, specific beliefs about taking medication (attitudes, subjective norms, perceived behavioral control), and intentions to take medication. Participants also completed measures of demographic variables (age, gender, education level, income, cardiovascular disease status). Data were analysed using path analysis controlling for country and demographic variables.Attitudes (β = .331, p0.001), subjective norms (β = .121, p=0.009), and beliefs about medication overuse (β = -.160, p0.001) were significant predictors of intentions to take medication. Treatment beliefs predicted intentions indirectly (β = .088, p0.001) through attitudes and subjective norms. There was also an indirect effect of beliefs about medication overuse on intentions (β = -.045, p=0.056), but the effect was small compared with the direct effect.The findings indicate the importance among FH patients of specific beliefs about taking medication and generalized beliefs about medication overuse and treatment in predicting medication intentions. When managing patients, clinicians should emphasize the efficacy of taking cholesterol-lowering drugs and the importance of treatment outcomes, and allay concerns about medication overuse.

ObjectiveTo determine physicians’ knowledge, awareness and preferences regarding the care of familial hypercholesterolaemia (FH) in the Asia-Pacific region.SettingA formal questionnaire was anonymously completed by physicians from different countries/regions in the Asia-Pacific. The survey sought responses relating to general familiarity, awareness of management guidelines, identification (clinical characteristics and lipid profile), prevalence and inheritance, extent of elevation in risk of cardiovascular disease (CVD) and practice on screening and treatment.ParticipantsPractising community physicians from Australia, Japan, Malaysia, South Korea, Philippines, Hong Kong, China, Vietnam and Taiwan were recruited to complete the questionnaire, with the UK as the international benchmark.Primary outcomeAn assessment and comparison of the knowledge, awareness and preferences of FH among physicians in 10 different countries/regions.Results1078 physicians completed the questionnaire from the Asia-Pacific region; only 34% considered themselves to be familiar with FH. 72% correctly described FH and 65% identified the typical lipid profile, with a higher proportion of physicians from Japan and China selecting the correct FH definition and lipid profile compared with those from Vietnam and Philippines. However, less than half of the physician were aware of national or international management guidelines; this was significantly worse than physicians from the UK (35% vs 61%, pConclusionsThe study identified important gaps, which are readily addressable, in the awareness and knowledge of FH among physicians in the region. Implementation of country-specific guidelines and extensive work in FH education and awareness programmes are imperative to improve the care of FH in the region.

Evidence for management of asthma comes from closely monitored efficacy trials done in highly selected patient groups. There is a need for randomised trials that are closer to usual clinical practice.We did an open-label, randomised, controlled, two-arm effectiveness trial at 74 general practice clinics in Salford and South Manchester, UK. Patients aged 18 years or older with a general practitioner's diagnosis of symptomatic asthma and on maintenance inhaler therapy were randomly assigned to initiate treatment with a once-daily inhaled combination of either 100 μg or 200 μg fluticasone furoate with 25 μg vilanterol or optimised usual care and followed up for 12 months. The primary endpoint was the percentage of patients who achieved an asthma control test (ACT) score of 20 or greater or an increase in ACT score from baseline of 3 or greater at 24 weeks (termed responders), in patients with a baseline ACT score less than 20 (the primary effectiveness analysis population). All effectiveness analyses were done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT01706198.Between Nov 12, 2012, and Dec 16, 2016, 4725 patients were enrolled and 4233 randomly assigned to initiate treatment with fluticasone furoate and vilanterol (n=2114) or usual care (n=2119). 1207 patients (605 assigned to usual care, 602 to fluticasone furoate and vilanterol) had a baseline ACT score greater than or equal to 20 and were thus excluded from the primary effectiveness analysis population. At week 24, the odds of being a responder were higher for patients who initiated treatment with fluticasone furoate and vilanterol than for those on usual care (977 [71%] of 1373 in the fluticasone furoate and vilanterol group vs 784 [56%] of 1399 in the usual care group; odds ratio [OR] 2·00 [95% CI 1·70-2·34], p0·0001). At week 24, the adjusted mean ACT score increased by 4·4 points from baseline in patients initiated with fluticasone furoate and vilanterol, compared with 2·8 points in the usual care group (difference 1·6 [95% CI 1·3-2·0], p0·0001). This result was consistent for the duration of the study. Pneumonia was uncommon, with no differences between groups; there was no difference in other serious adverse events between the groups.In patients with a general practitioner's diagnosis of symptomatic asthma and on maintenance inhaler therapy, initiation of a once-daily treatment regimen of combined fluticasone furoate and vilanterol improved asthma control without increasing the risk of serious adverse events when compared with optimised usual care.GlaxoSmithKline.

In randomized clinical trials, reduction in cardiovascular disease (CVD) risk with cholesterol-lowering drugs correlates with the LDL cholesterol decrease. However, because the majority have investigated a fixed statin dose, current guidelines disagree about the use of statin dose titration or non-statin adjunctive cholesterol-lowering drugs. We conducted a meta-analysis of all randomized controlled trials with CVD end-points, comparing two intensities of lipid-lowering regimens within the same population, using varying statins doses and/or potency, ezetimibe or PCSK9 inhibitors and compared the observed number of patients needed to be treated for 10 years to prevent one CVD event (NNT) with NNT predicted from trials of predominantly single-dose statin. Some 75439 participants in 10 randomized studies were included. The mean 10-year CVD risk in controls was around 50% and the incremental mean LDL cholesterol decrease 0.95 mmol/l (36.7 mg/dl). Observed NNT closely correlated with those predicted from predominantly single-dose statin trials [18.2 and 17.1; Pearson R=0.844 (P=0.001)]. When pre-treatment LDL cholesterol exceeded 4 mmol/l (155 mg/dl), achieving a target LDL cholesterol of 1.8 mmol/l (70 mg/dl) was the most effective strategy. At lower pre-treatment levels, fixed-dose statin equivalent to atorvastatin 80 mg daily was superior. The target of 40% reduction in non-high density lipoprotein cholesterol was least effective regardless of pre-treatment LDL cholesterol. We conclude that when initial LDL cholesterol exceeds 4 mmol/l and absolute CVD risk demands it, a target value of 1.8 mmol/l should be achieved, if necessary by adding ezetimibe and/or PCSK9 inhibitors to statin treatment.

Background: Statin therapy is recommended in type 2 diabetes (T2DM) although views on treatment intensity and therapeutic targets remain divided. Objectives: Our objectives were to compare the effects of high-intensity and moderate-intensity atorvastatin treatment on lipoprotein metabolism and inflammatory markers and how frequently treatment goals are met in high-risk T2DM patients. Methods: Patients with T2DM and albuminuria (urinary albumin:creatinine ratio >5 mg/mmol, total cholesterol

Familial hypercholesterolemia results from gene mutations approximately halving the number of functional LDL receptors in heterozygotes and a greater lack in homozygotes. Reduced receptor-mediated catabolism of LDL causes high plasma LDL cholesterol (LDL-C) and premature coronary artery disease. Statins lower plasma cholesterol by upregulating LDL receptor gene expression and are consequently relatively ineffective in homozygous familial hypercholesterolemia (HoFH). The standard treatment for HoFH is LDL apheresis combined with maximum tolerated potent statins, ezetimibe and bile acid sequestrants. In untreated HoFH, coronary heart disease usually develops in the first and second decade of life and often involves the aortic root and aortic valve. Peripheral vascular disease is common. Besides reduced receptor-mediated catabolism, there are other abnormalities in lipid metabolism in HoFH due to lack of LDL receptors. These include increased apoB turnover, raised lipoprotein(a) levels, reduced HDL cholester...

Objective Early diagnosis and treatment of heterozygous familial hypercholesterolaemia (HeFH) is known to be associated with reduced mortality from premature coronary artery disease, but HeFH remains underdiagnosed. This survey aims to determine knowledge and current management of HeFH in general practice. Setting An online questionnaire was administered to general practitioners’ (GPs’) in the North West of England to assess their knowledge and management of HeFH. Participants Practising GPs in the North West of England were contacted by email and invited to complete an online questionnaire. Recruitment discontinued when the target of 100 was reached. Primary outcome An assessment of the knowledge and current management of HeFH in GPs. Results 100 GP responses were analysed. Although only 39% considered themselves to have reasonable knowledge of HeFH, 89% knew that HeFH was a genetic disorder and 74% selected the correct lipid profile for diagnosing the condition. More than half (61%) were aware of current guidelines on HeFH. Gaps in knowledge were evident when only 30% correctly identified the prevalence of HeFH and half were not aware of the pattern of inheritance. Increased cardiovascular risk was underestimated by majority. 33% thought that they had HeFH patients in their practice confirming underdiagnosis of the condition. Statin therapy was recognised by 94% to be the right medication for treating HeFH. The majority (82%) regarded GPs to be the most effective healthcare professional for early recognition of HeFH. Conclusions GPs have an above-average knowledge of familial hypercholesterolaemia (FH) and almost universally consider that they have a key role in the early recognition of undiagnosed HeFH patients in the community. However, there are gaps in awareness that need to be addressed to further enhance the care of FH in the community.

Magnetic resonance spectroscopy (MRS) is a non-invasive method for quantitative estimation of liver fat. Knowledge of its imprecision, which comprises biological variability and measurement error, is required to design therapeutic trials with measurement of change. The role of adipocyte lipolysis in ectopic fat accumulation remains unclear. We examined the relationship between liver fat content and indices of lipolysis, and determine whether lipolysis reflects insulin resistance or metabolic liver disease. Imprecision of measurement of liver fat was estimated from duplicate measurements by MRS at one month intervals. Patients provided fasting blood samples and we examined the correlation of liver fat with indices of insulin resistance, lipolysis and metabolic liver disease using Kendall Tau statistics. The coefficient of variation of liver fat content was 14.8%. Liver fat was positively related to serum insulin (T = 0.48, p = 0.042), homeostasis model assessment (HOMA)-B% (T = −0.48, p = 0.042), and body mass index (BMI) (T = 0.59, p = 0.012); and inversely related to HOMA-S% (T = −0.48, p = 0.042), serum glycerol (T = −0.59, p = 0.014), and serum caeruloplasmin (T = 0.055, p = 0.047). Our estimate of total variability in liver fat content (14.8%) is nearly twice that of the reported procedural variability (8.5%). We found that liver fat content was significantly inversely related to serum glycerol but not to non-esterified fatty acids (NEFA), suggesting progressive suppression of lipolysis. Reduction of caeruloplasmin with increasing liver fat may be a consequence or a cause of hepatic steatosis.

Summary Objective Both cigarette smoking and use of exogenous hormones are associated with changes in regional distribution of body fat, but their combined effects are less investigated. We examined the interrelation between smoking, exogenous hormones and fat distribution in premenopausal and postmenopausal women. Method We used data from 20 962 women without known cardiovascular disease (CVD) who were employees of a major department store in Britain. They completed a health questionnaire and attended a clinical examination that included waist and hip circumference measurements. The cross-sectional analyses were conducted using linear regression models. Results Cigarette smoking, particularly smoking ≥20 cigarettes/day, was associated with larger waist circumference and higher waist/hip ratio (WHR) in pre- and postmenopausal women after adjusting for potential confounding factors (all P 0·05). Conclusion Although exogenous hormones use was related to a more favourable fat distribution in women, smoking was associated with greater abdominal fat accumulation.

Introduction Clinical trials have shown that apolipoprotein B100 (apoB) is better than calculated low-density lipoprotein cholesterol (c-LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) as a target for statin treatment. However, there are no published reports of how well these targets are reached in patients with more severe hyperlipidaemias than represented in trials, as seen in lipid clinics. Methods We audited 195 patients attending a tertiary centre lipid clinic, who had been treated with a statin for more than one year. We measured total cholesterol, HDL-cholesterol (HDL-C) and triglyceride and from these calculated LDL-cholesterol (LDL-C) and non-HDL-C. We determined the average measured apoB values, at critical target values of LDL-C and non-HDL-C, by linear regression and compared them with values of apoB considered equivalent to these cholesterol indexes by expert groups. We also assessed the number of patients, both before and after treatment, in whom c-LDL-C and non-HDL-C could not be calculated due to hypertriglyceridaemia. Results At the LDL-C target of 2.6 mmol L−1 and the non-HDL-C target of 3.4 mmol L−1, the measured apoB values were significantly higher than consensus apoB target values. The difference was most marked for c-LDL-C in hypertriglyceridaemic subjects and for non-HDL-C in patients without hypertriglyceridaemia. A similar pattern was seen using centile-derived consensus values but the differences were accentuated because this approach generates lower equivalent consensus apoB values. Conclusion ApoB offers a more consistent treatment target independent of hypertriglyceridaemia and would obviate technical problems related to high triglycerides.

OBJECTIVE: Women's cardiovascular risk factors, including inflammatory markers such as C-reactive protein (CRP) which is emerging as a major association with cardiovascular disease (CVD) risk, can be influenced by the oral contraceptive (OC) pill in premenopausal and hormone replacement (HR) in postmenopausal women and by central adiposity which is associated with a heightened inflammatory state. The interaction between central obesity and different hormone use in both pre and postmenopausal women has not previously been reported in a study spanning the whole age range associated with hormone use. DESIGN: Observational, cross-sectional study. PATIENTS: Only healthy women were included in this study. MEASUREMENTS: A total of 21,310 women aged 30-64 employed by Marks and Spencer participated. They completed a health questionnaire and were screened for CVD risk factors including blood pressure, weight, height, waist and hip circumference, lipids and lipoproteins, CRP and fibrinogen. RESULTS: Compared with non-users, women who took the OC or HR had significantly higher CRP levels. This was more marked than effects on other CVD risk factors. It was further compounded by the independent effect of increased waist circumference. The CRP increase was greatest (more than twice that of nonhormone users) in premenopausal women with the highest quartile of waist circumference who took the combined contraceptive pill. CONCLUSIONS: Women who received first the combined OC and then HR may be exposed over much of their life to high CRP levels aggravated by central obesity. The health consequences of this require further investigation.

BACKGROUND: Obesity increases cardiovascular risk through effects on blood pressure, lipoproteins, coagulation factors and inflammatory cytokines, but in women variation in fat distribution complicates these relationships. Central (maletype or visceral) obesity confers greater risk than the more generalised (female) type. This is recognised by the metabolic syndrome which employs waist circumference rather than body mass index (BMI). We examined the relationships of several indices of fat distribution with cardiovascular risk factors in a large cohort of UK women. MATERIAL AND METHODS: 13,389 female department store employees aged 30–65 years not receiving exogenous hormones completed a health questionnaire. Their blood pressure, weight, height, waist and hip circumference, serum cholesterol low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides, C-reactive protein (CRP) and plasma fibrinogen were measured. RE-SULTS: There was a progressive rise in blood pressure, total cholesterol, LDL-C, triglycerides, fibrinogen and CRP with age. After adjustment for these age effects, BMI was most closely related to blood pressure, whereas the waist to height ratio (WHTR) correlated more closely with the other risk factors than BMI, waist circumference or waist to hip ratio (WHPR). CONCLUSIONS: Inclusion of height in the definition of metabolic syndrome will produce a clearer association between waist circumference and cardiovascular risk factors. Hypertension may be linked to the metabolic syndrome by its association with general obesity rather than specifically by central obesity.

Background The aim of this study was to explore the influence of extended‐release niacin/laropiprant ( ERN / LRP ) versus placebo on high‐density lipoprotein ( HDL ) antioxidant function, cholesterol efflux, apolipoprotein B100 (apoB)‐containing lipoproteins, and mediators of vascular inflammation associated with 15% increase in high‐density lipoprotein cholesterol ( HDL ‐C). Study patients had persistent dyslipidemia despite receiving high‐dose statin treatment. Methods and Results In a randomized double‐blind, placebo‐controlled, crossover trial, we compared the effect of ERN / LRP with placebo in 27 statin‐treated dyslipidemic patients who had not achieved National Cholesterol Education Program‐ ATP III targets for low‐density lipoprotein cholesterol ( LDL ‐C). We measured fasting lipid profile, apolipoproteins, cholesteryl ester transfer protein ( CETP ) activity, paraoxonase 1 (PON1) activity, small dense LDL apoB (sd LDL ‐apoB), oxidized LDL (ox LDL ), glycated apoB (glyc‐apoB), lipoprotein phospholipase A2 (Lp‐ PLA 2), lysophosphatidyl choline (lyso‐ PC ), macrophage chemoattractant protein ( MCP 1), serum amyloid A ( SAA ) and myeloperoxidase ( MPO ). We also examined the capacity of HDL to protect LDL from in vitro oxidation and the percentage cholesterol efflux mediated by apoB depleted serum. ERN / LRP was associated with an 18% increase in HDL ‐C levels compared to placebo (1.55 versus 1.31 mmol/L, P LDL cholesterol, total serum apoB, lipoprotein (a), CETP activity, ox LDL , Lp‐ PLA 2, lyso‐ PC , MCP 1, and SAA , but no significant changes in glyc‐apoB or sd LDL ‐apoB concentration. There was a modest increase in cholesterol efflux function of HDL (19.5%, P =0.045), but no change in the antioxidant capacity of HDL in vitro or PON 1 activity. Conclusions ERN / LRP reduces LDL ‐associated mediators of vascular inflammation, but has varied effects on HDL functionality and LDL quality, which may counter its HDL ‐C‐raising effect. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01054508.

Summary objective Medroxyprogesterone (MP) was used as the progestogen in randomized clinical trials of postmenopausal hormone replacement on cardiovascular risk. To attempt to understand the lack of benefit in these trials, we have examined the effects of MP and two other progestogens, the less androgenic desogestrel (DG) and the more androgenic norethisterone (NE), on cardiovascular risk factors against a background of oestrogen therapy. design and measurements Thirty-four women were treated with conjugated equine oestrogens (CEE) 0·625 mg daily alone for 12 weeks, followed in random order by each of the three progestogens (DG 75 µg, MP 10 mg and NE 1 mg daily) given sequentially for three 12-week cycles while maintaining the same CEE treatment. We measured serum lipoproteins, paraoxonase activity, C-reactive protein (CRP), fibrinogen, fasting glucose and insulin levels at baseline, at the end of the oestrogen-only phase and at the end of each of the combined oestrogen and progestogen phases. results The addition of progestogens to CEE maintained the oestrogen-induced reduction in apolipoprotein B (apo B) and lipoprotein (a) [Lp(a)], and further lowered total cholesterol (P

Background: Aspirin and statins are the two drugs most commonly indicated for secondary prevention of atherosclerotic disease in the UK. Statin treatment, which is more expensive, is under‐prescribed. Aim: To assess the expenditure in Greater Manchester general practices on aspirin and statins. Design: Survey of general practice records. Methods: Practice registers were searched for patients receiving regular prescriptions for aspirin. For each patient, the next patient of the same sex, aged within ±5 years, not on aspirin, acted as a control. Details of all medications were recorded. In a sub‐study, records of 100 patients on aspirin were studied to determine indications for aspirin prescription. Results: There were 1003 (511 men, 492 women) in each group; mean age was 70 years in both groups. In the sub‐study, 79% of patients received aspirin for established vascular disease, 9% for hypertension, 5% for diabetes mellitus, 5% for unknown reasons and 2% for arthritis. Of the patients on aspirin, 67% received dispersible aspirin 75 mg/day. The rest were on higher doses (10%) or on more expensive preparations (22%), costing up to 22.4 p/day. The mean daily cost of aspirin was 1.7p. Dyspepsia treatment was received by 266 patients and 194 controls ( p

Both cigarette smoking and use of exogenous hormones are associated with changes in regional distribution of body fat, but their combined effects are less investigated. We examined the interrelation between smoking, exogenous hormones and fat distribution in premenopausal and postmenopausal women.We used data from 20, 962 women without known cardiovascular disease (CVD) who were employees of a major department store in Britain. They completed a health questionnaire and attended a clinical examination that included waist and hip circumference measurements. The cross-sectional analyses were conducted using linear regression models.Cigarette smoking, particularly smoking ≥20 cigarettes/day, was associated with larger waist circumference and higher waist/hip ratio (WHR) in pre- and postmenopausal women after adjusting for potential confounding factors (all P 0·001). Premenopausal women using combined oral contraceptive (COC) and postmenopausal women using oestrogen-only hormone replacement therapy (HRT) had lower WHR than non-hormone users in both smokers and nonsmokers. However, smokers had higher WHR than nonsmokers in both groups of hormone users and nonusers. There was no significant interaction between smoking and hormone use in premenopausal and postmenopausal women (P 0·05).Although exogenous hormones use was related to a more favourable fat distribution in women, smoking was associated with greater abdominal fat accumulation.

Although treatment with statins reduces cardiovascular (CV) events in patients with dyslipidemia, a residual 60 - 70% CV risk remains. This CV risk may be inversely related to high-density lipoprotein-cholesterol (HDL-C). Interest in niacin has re-emerged because of its HDL-C raising effects. The flushing associated with niacin which has previously affected patient compliance can now be significantly blocked with laropiprant (LRPT).This review aims to assess the efficacy, clinical effectiveness and safety of extended-release niacin (ERN) with LRPT. The authors searched PubMed and MEDLINE for literature published between January 2006 and November 2011, for efficacy, clinical effectiveness and safety reports of ERN with LRPT.Niacin has been shown to prevent CV events, reduce mortality and has beneficial effects on vascular endothelial function. Evidence suggests that this is due to its broad-spectrum lipid altering properties, including lowering lipoprotein (a) (Lp(a)), and its pleiotropic actions. While side effects associated with niacin have limited its use in the past, the extended-release formulations and co-administration of LRPT have increased its tolerability, particularly by reducing flushing. The authors advise that ERN should be used in patients with a high risk of cardiovascular disease, who have failed to reach conventional targets.

Introduction: Niacin is one of the oldest drugs used in the treatment of dyslipidemia. Previously its use has been limited because of excessive flushing. Now an agent laropiprant (LRP) has been developed, which blocks the flushing pathway. Therefore, it is time to collate available information to assess the safety and tolerability of combining niacin with LRP. Areas covered: The authors searched PubMed and MEDLINE for literature published between January 2006 and July 2011, for safety and tolerability reports of extended-release niacin (ERN) with LRP. Expert opinion: The addition of LRP to ERN, by reducing the side effect ‘flushing’, may enable lipidologists and physicians to use niacin more widely as part of lipid modification therapy, especially since the combination can be safely added to statins. However, it has to be accepted that the addition of LRP does not completely abolish flushing. The favorable safety profile supports the use of LRP to achieve higher therapeutic dosing of niacin.

Background Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease because of exposure to elevated low-density lipoprotein cholesterol (LDL-C) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for cardiovascular disease prevention, but the residual risk in HoFH remains high, emphasizing the need for additional therapies. In the present study, we evaluated the effect of serial infusions with CER-001, a recombinant human apolipoprotein A-I (apoA-I)–containing high-density lipoprotein–mimetic particle, on carotid artery wall dimensions in patients with HoFH. Methods and results Twenty-three patients (mean age 39.4 ± 13.5 years, mean LDL-C 214.2 ± 81.5 mg/dL) with genetically confirmed homozygosity or compound heterozygosity for LDLR , APOB , PCSK9 , or LDLRAP1 mutations received 12 biweekly infusions with CER-001 (8 mg/kg). Before and 1 hour after the first infusion, lipid values were measured. Magnetic resonance imaging (3-T magnetic resonance imaging) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. After CER-001 infusion, apoA-I increased from 114.8 ± 20.7 mg/dL to 129.3 ± 23.0 mg/dL. After 24 weeks, mean vessel wall area (primary end point) decreased from 17.23 to 16.75 mm 2 ( P = .008). A trend toward reduction of mean vessel wall thickness was observed (0.75 mm at baseline and 0.74 mm at follow-up, P = .0835). Conclusions In HoFH, 12 biweekly infusions with an apoA-I–containing high-density lipoprotein–mimetic particle resulted in a significant reduction in carotid mean vessel wall area, implying that CER-001 may reverse atherogenic changes in the arterial wall on top of maximal low-density lipoprotein–lowering therapy. This finding supports further clinical evaluation of apoA-I–containing particles in patients with HoFH.

The lack of cardiovascular benefit from postmenopausal hormone replacement therapy (HRT) in randomised controlled trials is not readily explained. The androgenic properties of progestogens could be crucial in understanding the results of these studies, all of which employed medroxyprogesterone. We have previously reported that medroxyprogesterone has some androgenic effects intermediate between those of the more androgenic norethisterone and the less androgenic desogestrel. To examine the androgenicity of progestogens further, we compared the effects of dydrogesterone (DGT) that is even less androgenic than desogestrel, and norethisterone (NET), on lipoproteins and inflammatory markers while maintaining the same oestrogen dose.In a crossover trial, 25 non-hysterectomised postmenopausal women were randomised to two preparations of HRT each for three 28-day treatment cycles. Both HRT regimens comprised oestradiol (1mg). One also included DGT (10mg) and the other NET (1mg). Oestradiol was taken continuously and the progestogens sequentially. Measurements were made at baseline and on the last day of the oestradiol phase and the last day of the progestogen phase in the third treatment cycle of each regimen.NET was more effective than DGT in significantly reducing lipoprotein (a) (p0.05). NET was, however, associated with significantly lower levels of high-density lipoprotein (HDL) cholesterol (p = 0.001) and triglycerides (p0.05). NET was less effective in opposing the oestrogen-related increase in C-reactive protein (CRP). Interleukin-6 levels did not change with either progestogen.The effect of androgenic progestogens on cardiovascular risk factors may not be as deleterious as previously assumed, especially if the lower HDL levels result from more efficient reverse cholesterol transport. The hormone related rise in C-reactive protein, without a corresponding increase in interleukin-6, may not represent a systemic inflammatory response.

Small-dense low-density lipoprotein (SD-LDL) is associated with coronary heart disease risk. Current methods for its quantification are expensive, complex and time-consuming. Plasma was adjusted to a density (D) of 1.044 g/ml in a volume of 0.18 ml and centrifuged in a Beckman Airfuge at 160 000 x g for 3 h 7 min and apolipoprotein B (apoB) then determined in the infranatant. Results were compared with centrifugation of 5 ml of plasma at D = 1.044 g/ml at 144 000 x g for 18 h in a preparative ultracentrifuge (UC). We obtained blood samples from healthy subjects (n = 73) and from dyslipidaemic patients (n = 112). SD-LDL apoB levels as determined using the UC method ranged from 0.01-0.43 g/l and there was a good correlation with Airfuge results (r = 0.925; p < 0.0001; n = 185). There was a mean difference of 0.0125 g/l between methods. SD-LDL apoB levels as determined using the Airfuge showed a reasonable agreement with results obtained using density gradient ultracentrifugation (r = 0.773; p < 0.01; n = 12). Airfuge results correlated directly with triglyceride concentration, in both healthy men (r = 0.296; p < 0.05) and dyslipidaemic men (r = 0.520; p < 0.001) and also in dyslipidaemic women (r = 0.463; p < 0.005). Airfuge results correlated inversely with high-density lipoprotein-cholesterol (HDL-C) concentration, in both healthy men (r = -0.237; p < 0.05) and dyslipidaemic men (r = -0.293; p < 0.005). Using a micro-method, we obtained results which establish that the Airfuge provides a more rapid and less expensive method for quantification of SD-LDL.