Lipoprotein(a) testing in lipid clinics across the UK: Results of a national survey.

Lipoprotein(a) is an independent risk factor for cardiovascular disease and its use is recommended in national and international guidelines for cardiovascular disease risk stratification. We undertook a survey to understand the availability and application of lipoprotein(a) measurement across UK lipid clinics. Fifty-three out of an estimated 200 lipid clinics (27%) provided responses. 81% of fifty-three clinics had access to lipoprotein(a) measurement. 27 clinics disclosed the number of lipoprotein(a) tests ordered annually with approximately half of the clinics (52%) requesting 0-250 tests per year. 60% measured lipoprotein(a) once per patient and the leading indication was a personal or family history of premature history of cardiovascular disease in those <60 years old. 63% of clinics that provided comments with lipoprotein(a) results graded cardiovascular risk as per the HEART UK consensus statement. 60% of clinics performed family cascade testing on lipoprotein(a) results ≥200nmol/L. Lipoprotein(a) was reported in nmol/L, mg/dL or mg/L by 48%, 24% and 28% of responding clinics, respectively. National effort is required to provide universal access to Lipoprotein(a) measurement and to harmonise the clinical application of this data.

The current status of lipoprotein (a) measurement in clinical biochemistry laboratories in the UK: Results of a 2021 national survey.

BACKGROUND: Lipoprotein(a) (Lp(a)) is now established as a causal risk factor for cardiovascular disease (CVD) and accurate laboratory measurement is of pivotal importance in reducing Lp(a) associated risk. The consensus statement by HEART UK in 2019 included recommendations to improve standardisation of clinical laboratory measurement and reporting of Lp(a). METHODS: A 16 question, electronic audit survey was circulated to 190 accredited clinical biochemistry laboratories to assess the adoption of these recommendations in the UK. RESULTS: Responses were received from 65 of 190 laboratories (34%). Only 5 (8%) did not offer Lp(a) measurement. Of those providing the test, 23% (n = 14) offered an in-house service (IHS), the remaining laboratories (77%; n = 46) used an external referral service (ERS). The majority (10 of 14 or 71%) of IHS laboratories responded with details of their method, stating whether it minimised sensitivity to the effect of Lp(a) isoform size and used calibrators certified for traceability to the WHO/IFCC reference material, however, only a minority ERS laboratories (13 of the 46 or 28%) were able to specify the method used by their referral laboratory. Of the laboratories who specified their reporting units, 6 of 10 IHS and 7 of 23 ERS laboratories reported in nmol/L. Among the 60 laboratories who responded, the HEART UK recommendations appear to have been adopted in full by only 3 IHS laboratories. CONCLUSIONS: Further efforts are needed to standardise the measurement and reporting of Lp(a) so that results and interpretation are comparable across clinical biochemistry laboratories in the UK.

Severe Hypertriglyceridaemia and Chylomicronaemia Syndrome-Causes, Clinical Presentation, and Therapeutic Options.

We have reviewed the genetic basis of chylomicronaemia, the difference between monogenic and polygenic hypertriglyceridaemia, its effects on pancreatic, cardiovascular, and microvascular complications, and current and potential future pharmacotherapies. Severe hypertriglyceridaemia (TG > 10 mmol/L or 1000 mg/dL) is rare with a prevalence of <1%. It has a complex genetic basis. In some individuals, the inheritance of a single rare variant with a large effect size leads to severe hypertriglyceridaemia and fasting chylomicronaemia of monogenic origin, termed as familial chylomicronaemia syndrome (FCS). Alternatively, the accumulation of multiple low-effect variants causes polygenic hypertriglyceridaemia, which increases the tendency to develop fasting chylomicronaemia in presence of acquired factors, termed as multifactorial chylomicronaemia syndrome (MCS). FCS is an autosomal recessive disease characterized by a pathogenic variant of the lipoprotein lipase (LPL) gene or one of its regulators. The risk of pancreatic complications and associated morbidity and mortality are higher in FCS than in MCS. FCS has a more favourable cardiometabolic profile and a low prevalence of atherosclerotic cardiovascular disease (ASCVD) compared to MCS. The cornerstone of the management of severe hypertriglyceridaemia is a very-low-fat diet. FCS does not respond to traditional lipid-lowering therapies. Several novel pharmacotherapeutic agents are in various phases of development. Data on the correlation between genotype and phenotype in FCS are scarce. Further research to investigate the impact of individual gene variants on the natural history of the disease, and its link with ASCVD, microvascular disease, and acute or recurrent pancreatitis, is warranted. Volanesorsen reduces triglyceride concentration and frequency of pancreatitis effectively in patients with FCS and MCS. Several other therapeutic agents are in development. Understanding the natural history of FCS and MCS is necessary to rationalise healthcare resources and decide when to deploy these high-cost low-volume therapeutic agents.

Derivation and comparison of formulae for the adjustment of total calcium.

Background: Free ionized calcium (Ca2+) is the biologically active component of total calcium (TCa) and hence responsible for its biological action. TCa is routinely adjusted for albumin using several formulae (e.g. James, Orell, Payne and Berry) to more closely reflect Ca2+. Here, we derive a novel formula to estimate Ca2+ and compare its performance to established formulae. Methods: Cohort for prediction of Ca2+: 2806 serum samples (TCa) taken contemporaneously with blood gas samples (Ca2+) at Imperial College Healthcare NHS Trust were used to derive formulae to estimate Ca2+ using multivariable linear regression. Cohort for prediction of PTH: Performance of novel and existing formulae to predict PTH in 5510 patients was determined by Spearman correlation. Results: Ca2+ prediction Cohort: Adjusted calcium (r2 = 0.269) was less strongly associated with Ca2+, than TCa (r2 = 0.314). Prediction of Ca2+ from a newly derived formula incorporating TCa, potassium, albumin, and hematocrit had an improved r2 of 0.327, whereas inclusion of all available parameters increased the r2 further to 0.364. Of the established formulae, James performed best in predicting Ca2+ (r2 = 0.27). PTH prediction cohort: Berry resulted in higher whereas Orell in lower adjusted calcium levels. Prediction of PTH was strongest in the setting of hypercalcemia, with James having the highest Spearman correlation coefficient (+0.496) similar to including all parameters (+0.499). Conclusion: Adjustment of calcium for albumin using established formulae does not always outperform unadjusted TCa in the reflection of Ca2+. Further prospective studies are needed to optimise adjustment of TCa and to establish bounds for validity.

The effect of adjusting LDL-cholesterol for Lp(a)-cholesterol on the diagnosis of familial hypercholesterolaemia.

BACKGROUND: Familial hypercholesterolaemia (FH) diagnostic tools help prioritise patients for genetic testing and include LDL-C estimates commonly calculated using the Friedewald equation. However, cholesterol contributions from lipoprotein(a) (Lp(a)) can overestimate 'true' LDL-C, leading to potentially inappropriate clinical FH diagnosis. OBJECTIVE: To assess how adjusting LDL-C for Lp(a)-cholesterol affects FH diagnoses using Simon Broome (SB) and Dutch Lipid Clinic Network (DLCN) criteria. METHODS: Adults referred to a tertiary lipid clinic in London, UK were included if they had undergone FH genetic testing based on SB or DLCN criteria. LDL-C was adjusted for Lp(a)-cholesterol using estimated cholesterol contents of 17.3%, 30% and 45%, and the effects of these adjustments on reclassification to 'unlikely' FH and diagnostic accuracy were determined. RESULTS: Depending on the estimated cholesterol content applied, LDL-C adjustment reclassified 8-23% and 6-17% of patients to 'unlikely' FH using SB and DLCN criteria, respectively. The highest reclassification rates were observed following 45% adjustment in mutation-negative patients with higher Lp(a) levels. This led to an improvement in diagnostic accuracy (46% to 57% with SB, and 32% to 44% with DLCN following 45% adjustment) through increased specificity. However all adjustment factors led to erroneous reclassification of mutation-positive patients to 'unlikely' FH. CONCLUSION: LDL-C adjustment for Lp(a)-cholesterol improves the accuracy of clinical FH diagnostic tools. Adopting this approach would reduce unnecessary genetic testing but also incorrectly reclassify mutation-positive patients. Health economic analysis is needed to balance the risks of over- and under-diagnosis before LDL-C adjustments for Lp(a) can be recommended.

National Institute for Health and Care Excellence guidelines for lipid management.

This article provides a summary of the available lipid-lowering therapies in the UK and how they fit into national guidelines. In addition, comparison is made between the current National Institute for Health and Care Excellence lipid modification guidelines and international guidance such as those published by the European Society of Cardiology/European Atherosclerosis Society and American Heart Association/American College of Cardiology.

A Case Series Assessing the Effects of Lomitapide on Carotid Intima-Media Thickness in Adult Patients with Homozygous Familial Hypercholesterolaemia in a Real-World Setting.

INTRODUCTION: Homozygous familial hypercholesterolaemia (HoFH) is characterised by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and results from multiple mutations in genes affecting the LDL receptor pathway. Patients are at risk of premature atherosclerotic cardiovascular disease (ASCVD) and premature death. Lomitapide is a microsomal triglyceride transfer protein inhibitor developed to treat HoFH, but cardiovascular outcome data are lacking. METHODS: We evaluated detailed data from five HoFH patients and one patient with heterozygous FH (HeFH) and a very severe phenotype. We also analysed confirmatory data from a further 8 HoFH cases. In total, we analysed data from patients in seven global centres in six countries who were all treated with lomitapide with long-term follow-up. Carotid intima-media thickness (CIMT) imaging was recorded on an ad hoc basis to monitor ASCVD in HoFH. RESULTS: Lomitapide resulted in marked decreases in LDL-C of 56.8-93.9% [77.7-93.9% in the 6 initial cases (mean nadir 64.8 ± 30.1 mg/dL); 56.8-86.0% in the 8 confirmatory cases (mean nadir 131.4 ± 38.2 mg/dL)]. CIMT regressed in 50% of cases (mean follow-up 5.0 ± 3.1 years in initial six cases, and 4.4 ± 1.4 years in confirmatory cases). In the remaining patients, CIMT showed little further change. In patients where assessments of plaque area were available, regression or stabilisation in CIMT was accompanied by clinically significant regression of plaque area. CONCLUSIONS: Lomitapide reduces LDL-C levels in patients with HoFH and severe LDL-C phenotypes, and results in stabilisation and/or regression of CIMT, which is an established marker of ASCVD risk. Additional data are needed to determine if this confers a survival benefit in these very high-risk patients.

Lipid lowering with inclisiran: a real-world single-centre experience.

OBJECTIVE: The reduction in circulating low-density lipoprotein cholesterol (LDL-c) is the primary aim of lipid-lowering therapies as a method of atherosclerotic cardiovascular disease risk reduction. Inclisiran is a new and potent lipid-lowering drug that is shown to be effective in reducing LDL-c in randomised controlled trials, however, real-world data of its use are not yet known. We sought to analyse the early effects of this drug in a tertiary centre lipid and cardiovascular risk clinic. METHODS: We performed a retrospective analysis of the first 80 patients who received a single dose of inclisiran at our lipid clinic between 1 December 2021 and 1 September 2022. Data were collected using electronic healthcare records. Baseline blood tests were taken prior to start of treatment and were repeated at 2 months follow-up. Data on adverse events were also recorded. RESULTS: At 2 months after treatment initiation, mean baseline LDL-c fell from 3.5±1.1 mmol/L by 48.6% to 1.8±1.0 mmol/L and total cholesterol from 5.7±1.3 mmol/L by 33.3% to 3.8±1.1 mmol/L (both p<0.0001). Mean high-density lipoprotein-c rose by 7.7% to 1.4±0.4 mmol/L (p=0.02) and median triglycerides fell by 31.3% to 1.1 mmol/L (IQR 0.9-2) (p=0.001). Adverse events (injection site reaction, fatigue and headache) were recorded in three patients and all had self-resolved by time of follow-up. CONCLUSION: Inclisiran use in line with National Institute for Health and Care Excellence guidelines led to significant lowering of LDL-c at 2 months, with efficacy similar to that reported in trials with good tolerability.

Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment.

BACKGROUND: Most people who begin statins abandon them, most commonly because of side effects. OBJECTIVES: The purpose of this study was to assess daily symptom scores on statin, placebo, and no treatment in participants who had abandoned statins. METHODS: Participants received 12 1-month medication bottles, 4 containing atorvastatin 20 mg, 4 placebo, and 4 empty. We measured daily symptom intensity for each using an app (scale 1-100). We also measured the "nocebo" ratio: the ratio of symptoms induced by taking statin that was also induced by taking placebo. RESULTS: A total of 60 participants were randomized and 49 completed the 12-month protocol. Mean symptom score was 8.0 (95% CI: 4.7-11.3) in no-tablet months. It was higher in statin months (16.3; 95% CI: 13.0-19.6; P < 0.001), but also in placebo months (15.4; 95% CI: 12.1-18.7; P < 0.001), with no difference between the 2 (P = 0.388). The corresponding nocebo ratio was 0.90. In the individual-patient daily data, neither symptom intensity on starting (OR: 1.02; 95% CI: 0.98-1.06; P = 0.28) nor extent of symptom relief on stopping (OR: 1.01; 95% CI: 0.98-1.05; P = 0.48) distinguished between statin and placebo. Stopping was no more frequent for statin than placebo (P = 0.173), and subsequent symptom relief was similar between statin and placebo. At 6 months after the trial, 30 of 60 (50%) participants were back taking statins. CONCLUSIONS: The majority of symptoms caused by statin tablets were nocebo. Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo. (Self-Assessment Method for Statin Side-effects Or Nocebo [SAMSON]; NCT02668016).

The use of whole blood capillary samples to measure 15 analytes for a home-collect biochemistry service during the SARS-CoV-2 pandemic: A proposed model from North West London Pathology.

BACKGROUND: The COVID-19 pandemic has drastically changed the delivery of secondary care services. Self-collection of capillary blood at home can facilitate the monitoring of patients with chronic disease to support virtual clinics while mitigating the risk of SARS-CoV-2 infection and transmission. OBJECTIVE: To investigate the comparability of whole blood capillary and plasma venous samples for 15 routinely used biochemical analytes and to develop and pilot a user-friendly home-collection kit to support virtual outpatient clinical services. METHODS: To investigate the comparability of whole blood capillary and plasma venous samples for 15 routinely requested biochemical analytes, simultaneous samples of venous and capillary blood were collected in EDTA and lithium-heparin plasma separation tubes that were of 4-6 mL and 400-600 µL draw volume, respectively. Venous samples were analysed within 4 h of collection while capillary samples were kept at ambient temperature for three days until centrifugation and analysis. Analyte results that were comparable between the matrices were then piloted in a feasibility study in three outpatient clinical services. RESULTS: HbA1c, lipid profile and liver function tests were considered comparable and piloted in the patient feasibility study. The home-collect kit demonstrated good patient usability. CONCLUSION: Home collection of capillary blood could be a clinically-useful tool to deliver virtual care to patients with chronic disease.

Lp(a): When and how to measure it.

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.

Managing hyperlipidaemia in patients with COVID-19 and during its pandemic: An expert panel position statement from HEART UK.

The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes Coronavirus Disease 2019 (COVID-19) has resulted in a pandemic. SARS-CoV-2 is highly contagious and its severity highly variable. The fatality rate is unpredictable but is amplified by several factors including advancing age, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension and obesity. A large proportion of patients with these conditions are treated with lipid lowering medication and questions regarding the safety of continuing lipid-lowering medication in patients infected with COVID-19 have arisen. Some have suggested they may exacerbate their condition. It is important to consider known interactions with lipid-lowering agents and with specific therapies for COVID-19. This statement aims to collate current evidence surrounding the safety of lipid-lowering medications in patients who have COVID-19. We offer a consensus view based on current knowledge and we rated the strength and level of evidence for these recommendations. Pubmed, Google scholar and Web of Science were searched extensively for articles using search terms: SARS-CoV-2, COVID-19, coronavirus, Lipids, Statin, Fibrates, Ezetimibe, PCSK9 monoclonal antibodies, nicotinic acid, bile acid sequestrants, nutraceuticals, red yeast rice, Omega-3-Fatty acids, Lomitapide, hypercholesterolaemia, dyslipidaemia and Volanesorsen. There is no evidence currently that lipid lowering therapy is unsafe in patients with COVID-19 infection. Lipid-lowering therapy should not be interrupted because of the pandemic or in patients at increased risk of COVID-19 infection. In patients with confirmed COVID-19, care should be taken to avoid drug interactions, between lipid-lowering medications and drugs that may be used to treat COVID-19, especially in patients with abnormalities in liver function tests.

The effects of dyslipidaemia and cholesterol modulation on erythrocyte susceptibility to malaria parasite infection.

BACKGROUND: Malaria disease commences when blood-stage parasites, called merozoites, invade human erythrocytes. Whilst the process of invasion is traditionally seen as being entirely merozoite-driven, emerging data suggests erythrocyte biophysical properties markedly influence invasion. Cholesterol is a major determinant of cell membrane biophysical properties demanding its interrogation as a potential mediator of resistance to merozoite invasion of the erythrocyte. METHODS: Biophysical measurements of erythrocyte deformability by flicker spectroscopy were used to assess changes in erythrocyte bending modulus on forced integration of cholesterol and how these artificial changes affect invasion by human Plasmodium falciparum merozoites. To validate these observations in a natural context, either murine Plasmodium berghei or human Plasmodium falciparum merozoites were tested for their ability to invade erythrocytes from a hypercholesterolaemic mouse model or human clinical erythrocyte samples deriving from patients with a range of serum cholesterol concentrations, respectively. RESULTS: Erythrocyte bending modulus (a measure of deformability) was shown to be markedly affected by artificial modulation of cholesterol content and negatively correlated with merozoite invasion efficiency. In an in vitro infection context, however, erythrocytes taken from hypercholesterolaemic mice or from human clinical samples with varying serum cholesterol levels showed little difference in their susceptibility to merozoite invasion. Explaining this, membrane cholesterol levels in both mouse and human hypercholesterolaemia erythrocytes were subsequently found to be no different from matched normal serum controls. CONCLUSIONS: Based on these observations, serum cholesterol does not appear to impact on erythrocyte susceptibility to merozoite entry. Indeed, no relationship between serum cholesterol and cholesterol content of the erythrocyte is apparent. This work, nonetheless, suggests that native polymorphisms which do affect membrane lipid composition would be expected to affect parasite entry. This supports investigation of erythrocyte biophysical properties in endemic settings, which may yet identify naturally protective lipid-related polymorphisms.

HEART UK consensus statement on Lipoprotein(a): A call to action.

Lipoprotein(a), Lp(a), is a modified atherogenic low-density lipoprotein particle that contains apolipoprotein(a). Its levels are highly heritable and variable in the population. This consensus statement by HEART UK is based on the evidence that Lp(a) is an independent cardiovascular disease (CVD) risk factor, provides recommendations for its measurement in clinical practice and reviews current and emerging therapeutic strategies to reduce CVD risk. Ten statements summarise the most salient points for practitioners and patients with high Lp(a). HEART UK recommends that Lp(a) is measured in adults as follows: 1) those with a personal or family history of premature atherosclerotic CVD; 2) those with first-degree relatives who have Lp(a) levels >200 nmol/l; 3) patients with familial hypercholesterolemia; 4) patients with calcific aortic valve stenosis and 5) those with borderline (but <15%) 10-year risk of a cardiovascular event. The management of patients with raised Lp(a) levels should include: 1) reducing overall atherosclerotic risk; 2) controlling dyslipidemia with a desirable non-HDL-cholesterol level of <100 mg/dl (2.5 mmol/l) and 3) consideration of lipoprotein apheresis.

Lipoprotein apheresis efficacy, challenges and outcomes: A descriptive analysis from the UK Lipoprotein Apheresis Registry, 1989-2017.

BACKGROUND AND AIMS: In 2008, the National Institute of Health and Care Excellence in the UK recommended that patients undergoing lipoprotein apheresis (LA) should be included in an anonymised registry. The UK Lipoprotein Apheresis Registry was subsequently established in 2011. METHODS: Between 2011 and 2017, data was entered retrospectively and prospectively by seven LA centres in the UK for 151 patients. Twenty-two patients were involved in a research study and were therefore excluded from the analysis. Observational data was analysed for the remaining 129 patients. RESULTS: Most patients had heterozygous familial hypercholesterolaemia (HeFH) (45.0%); 23.3% had homozygous FH (HoFH); 7.8% had hyper-lipoproteinaemia (a) (Lp(a)) and 24.0% had other forms of dyslipidaemia. Detailed treatment data is available for 63 patients relating to 348 years of LA treatment. The number of years of treatment per patient ranged from 1 to 15. The mean reduction in interval mean LDL-C from the pre-procedure baseline was 43.14%. The mean reduction in interval mean Lp(a) from baseline was 37.95%. The registry data also shows a 62.5% reduction in major adverse cardiovascular events (MACE) between the 2 years prior to, and the first 2 years following introduction of LA. CONCLUSIONS: The data generated by the UK Lipoprotein Apheresis Registry demonstrates that LA is a very efficient method of reducing LDL-C and Lp(a) and lowers the incidence rate of MACE. LA is an important tool in the management of selected patients with HoFH and drug-resistant dyslipidaemias.

Management of hypertriglyceridaemic pancreatitis in the acute setting and review of literature.

Acute pancreatitis (AP) is a potentially life-threatening complication of severe hypertriglyceridaemia, which is the third most common cause of AP after gallstone disease and alcohol excess. Standard therapy involves the use of lipid-lowering agents, low-molecular-weight heparin and insulin infusion. In some cases, when standard medical therapies fail, non-pharmacological methods based on the removal of triglycerides with therapeutic plasma exchange can provide positive results in the acute phase. There are currently no guidelines covering management in the acute phase, however, these approaches should be considered in severe or very severe hypertriglyceridaemia. Here, we report the case of a 37-year-old man with recurrent AP due to hypertriglyceridaemia and review the literature.