International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.

This contemporary, international, evidence-informed guidance aims to achieve the greatest good for the greatest number of people with familial hypercholesterolaemia (FH) across different countries. FH, a family of monogenic defects in the hepatic LDL clearance pathway, is a preventable cause of premature coronary artery disease and death. Worldwide, 35 million people have FH, but most remain undiagnosed or undertreated. Current FH care is guided by a useful and diverse group of evidence-based guidelines, with some primarily directed at cholesterol management and some that are country-specific. However, none of these guidelines provides a comprehensive overview of FH care that includes both the lifelong components of clinical practice and strategies for implementation. Therefore, a group of international experts systematically developed this guidance to compile clinical strategies from existing evidence-based guidelines for the detection (screening, diagnosis, genetic testing and counselling) and management (risk stratification, treatment of adults or children with heterozygous or homozygous FH, therapy during pregnancy and use of apheresis) of patients with FH, update evidence-informed clinical recommendations, and develop and integrate consensus-based implementation strategies at the patient, provider and health-care system levels, with the aim of maximizing the potential benefit for at-risk patients and their families worldwide.

The scientific basis and future of lipoprotein apheresis.

Lipoprotein apheresis plays a vital role in the management of the severe hyperlipidemias that predispose to atherosclerosis. Determinants of efficacy are the acute reduction in lipoproteins achieved by each apheresis procedure, their frequency, and the fractional catabolic rates and hence pool sizes of low-density lipoprotein (LDL) or lipoprotein (a) (Lp(a)) of the patient being treated. A useful criterion of the efficacy of apheresis plus lipid-lowering drug therapy is the decrease in the interval (time-averaged) mean of serum total or LDL cholesterol or Lp(a) between procedures, expressed as the percent decrease in the interval means below the maximal levels of these lipoproteins when off all treatment. Recent advances in lipid-lowering drug therapy may diminish the use of lipoprotein apheresis but will not abolish its unique role as a therapeutic "last chance saloon," especially for children and pregnant women with homozygous familial hypercholesterolemia.

Use of apheresis in the age of new therapies for familial hypercholesterolaemia.

PURPOSE OF REVIEW: Lipoprotein apheresis has been first line therapy for homozygous familial hypercholesterolaemia (FH) and other severe and refractory forms of dyslpidaemia for over 40 years but the recent advent of novel and potent LDL-lowering compounds necessitates a reappraisal of its role. RECENT FINDINGS: During the past decade a substantial amount of evidence has accumulated describing the effect of LDL-lowering with apheresis and conventional drug therapy upon the cardiovascular outcomes associated with homozygous and statin-refractory heterozygous FH. This has necessitated re-defining the target levels of LDL cholesterol needed to arrest progression of atherosclerosis in these situations. At the same time, evidence has accrued regarding the pathogenicity of raised levels of lipoprotein (a) and the promising role of apheresis in mitigating the adverse effects of the latter. The latest advance in treatment has been the introduction of three classes of novel and potent LDL-lowering compounds in the shape of inhibitors of Propertin convertase subtilisin kexin 9 (PCSK9), microsomal triglyceride transfer protein and angiopoietin-like 3. SUMMARY: These recent developments raise the question of whether these compounds will be used as adjuvants to bolster lipoprotein apheresis in FH homozygotes or whether they will render it obsolete, as is already occurring with PCSK9 inhibitors in FH heterozygotes.

FH through the retrospectoscope.

After training as a gastroenterologist in the UK, the author became interested in lipidology while he was a research fellow in the USA and switched careers after returning home. Together with Nick Myant, he introduced the use of plasma exchange to treat familial hypercholesterolemia (FH) homozygotes and undertook non-steady state studies of LDL kinetics, which showed that the fractional catabolic rate of LDL remained constant irrespective of pool size. Subsequent steady-state turnover studies showed that FH homozygotes had an almost complete lack of receptor-mediated LDL catabolism, providing in vivo confirmation of the Nobel Prize-winning discovery by Goldstein and Brown that LDL receptor dysfunction was the cause of FH. Further investigation of metabolic defects in FH revealed that a significant proportion of LDL in homozygotes and heterozygotes was produced directly via a VLDL-independent pathway. Management of heterozygous FH has been greatly facilitated by statins and proprotein convertase subtilisin/kexin type 9 inhibitors but remains dependent upon lipoprotein apheresis in homozygotes. In a recent analysis of a large cohort treated with a combination of lipid-lowering measures, survival was markedly enhanced in homozygotes in the lowest quartile of on-treatment serum cholesterol. Emerging therapies could further improve the prognosis of homozygous FH; whereas in heterozygotes, the current need is better detection.

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.

Current Role of Lipoprotein Apheresis.

PURPOSE OF REVIEW: Lipoprotein apheresis is a very efficient but time-consuming and expensive method of lowering levels of low-density lipoprotein cholesterol, lipoprotein(a)) and other apoB containing lipoproteins, including triglyceride-rich lipoproteins. First introduced almost 45 years ago, it has long been a therapy of "last resort" for dyslipidaemias that cannot otherwise be managed. In recent years new, very potent lipid-lowering drugs have been developed and the purpose of this review is to define the role of lipoprotein apheresis in the current setting. RECENT FINDINGS: Lipoprotein apheresis still plays an important role in managing patients with homozygous FH and some patients with other forms of hypercholesterolaemia and cardiovascular disease. In particular, patients not achieving treatment goals despite modern lipid-lowering drugs, either because these are not tolerated or the response is insufficient. Recently, lipoprotein(a) has emerged as an important cardiovascular risk factor and lipoprotein apheresis has been used to decrease lipoprotein(a) concentrations in patients with marked elevations and cardiovascular disease. However, there is considerable heterogeneity concerning the recommendations by scientific bodies as to which patient groups should be treated with lipoprotein apheresis. Lipoprotein apheresis remains an important tool for the management of patients with severe drug-resistant dyslipidaemias, especially those with homozygous FH.

Black Pastors' Views on preaching about sex: barriers, facilitators, and opportunities for HIV prevention messaging.

OBJECTIVES: Despite the disproportionately high rates of heterosexually transmitted HIV infection among US Blacks and ongoing need for effective inexpensive behavioral interventions, the use of sermons as an HIV prevention tool in Black churches has received little research attention. The Black church plays an important role in Black communities and is a potential ally in development and delivery of sexual risk prevention messages. The objective of this study was to examine Black pastors' thoughts about whether sermons should address issues related to heterosexual relationships - and the barriers and facilitators to discussing these topics in a sermon setting. DESIGN: We conducted in-depth semi-structured, individual interviews among 39 pastors of Black churches in North Carolina and analyzed the interview data using thematic analysis strategies based on grounded theory. RESULTS: Pastors expressed widely ranging opinions, especially about discussion of condom use, but generally agreed that sermons should discuss marriage, abstinence, monogamy, dating, and infidelity - behaviors that impact sexual networks and HIV transmission. The major barriers to incorporation of these subjects into sermons include the extent to which a concept undermines their religious beliefs and uncertainty about how to incorporate it. However, scriptural support for a prevention message and the pastor's perception that the message is relevant to the congregation facilitate incorporation of related topics into sermons. CONCLUSIONS: These findings have implications for the potential utility of sermons as an HIV prevention tool and suggest that it is possible for public health professionals and pastors of Black churches to form partnerships to develop messages that are consonant with pastors' religious convictions as well as public health recommendations.

Atherosclerosis in cholesterol-fed rabbits and in homozygous and heterozygous LDL receptor-deficient humans.

A phenocopy is an environmentally-defined phenotype that mimics another, genetically-determined phenotype. The severity of hypercholesterolaemia, extent of down regulation of LDL receptor expression and aortic root localisation of atherosclerosis in cholesterol-fed rabbits strikingly resemble the cardinal features of homozygous familial hypercholesterolaemia (FH) in humans, suggesting that the former is a phenocopy of the latter. This review compares the metabolic and pathological consequences of induced hypercholesterolaemia in rabbits with those of homozygous FH and contrasts their ease of reversibility on resumption of a normal diet with the refractoriness to lipid-lowering therapy of homozygotes, in whom major adverse cardiovascular events and survival depend upon the prevailing level of serum cholesterol. The monofactorial nature of the atherosclerosis in both situations corroborates Anitschkow's concept that "Cholesterin ist alles." In contrast, atherosclerosis in heterozygous FH differs in several respects from that of homozygotes, notably the lack of aortic root involvement and in its multifactorial aetiology, with raised LDL cholesterol, male gender, low HDL cholesterol and raised lipoprotein (a) all contributing to its clinical expression. In angiographic trials of LDL-lowering therapy regression of coronary lesions was observed in FH heterozygotes whereas they progressed in non-FH subjects. Similarly, carotid artery plaques progressed less in FH heterozygotes than in non-FH subjects, in both instances despite FH patients having higher LDL cholesterol levels on treatment. These findings suggest that, compared with non-FH subjects, atherosclerotic lesions in FH heterozygotes may be hyper-responsive to LDL-lowering therapy, whereas treatment of homozygous FH remains a major challenge.

Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol.

Aims: Homozygous familial hypercholesterolaemia (FH) is a rare inherited disorder characterized by extreme hypercholesterolaemia from birth, accelerated atherosclerosis, and premature death. Many forms of lipid-lowering therapies have been used in the past, but definitive evidence of benefit has been lacking. We therefore undertook a retrospective survey of lipid levels and clinical outcomes of FH homozygotes treated with a combination of lipid-lowering measures between 1990 and 2014 in South Africa and the UK. Methods and results: We divided 133 previously statin-naive homozygotes into quartiles according to their on-treatment levels of serum cholesterol and compared the occurrence of any death, cardiovascular death, and major adverse cardiovascular events (MACE) between the quartiles during 25 years of follow-up, using Cox and competing risks regression analysis. Patients in Quartile 4, with an on-treatment serum cholesterol >15.1 mmol/L, had a hazard ratio of 11.5 for any death compared with those in Quartile 1, with an on-treatment cholesterol of < 8.1 mmol/L. Those in Quartiles 2 and 3 combined, with on-treatment cholesterol of 8.1-15.1 mmol/L had a hazard ratio of 3.6 compared with Quartile 1. These differences were statistically significant (P < 0.001) and remained so after adjustments for confounding factors (P = 0.04). Significant differences between quartiles were also evident for cardiovascular deaths and MACE. Conclusion: These findings provide unequivocal evidence that the extent of reduction of serum cholesterol achieved by a combination of therapeutic measures, including statins, ezetimibe, lipoprotein apheresis, and evolocumab, is a major determinant of survival in homozygous FH.

HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom.

This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK.

Improved cardiovascular outcomes following temporal advances in lipid-lowering therapy in a genetically-characterised cohort of familial hypercholesterolaemia homozygotes.

BACKGROUND AND AIMS: There is a paucity of data concerning the influence of lipid-lowering therapy on cardiovascular (CV) outcomes in patients with homozygous familial hypercholesterolaemia (FH). To redress this a retrospective analysis was undertaken of the demographic features, lipid levels, low density lipoprotein receptor and Autosomal Recessive Hypercholesterolaemia gene mutations, CV outcomes and vital status of 44 FH homozygotes referred to a single centre in the UK between 1964 and 2014. METHODS: Data were obtained from past publications, case records and death certificates. Differences in categorical and continuous variables between living and dead patients were analysed using Fisher's exact test and an independent t-test respectively. RESULTS: During the 50 years covered by this survey 13 patients have died, 30 are still alive and 1 was lost to follow up. The mean age of Alive patients was 32.6 ± 11.5 versus 28.3 ± 14.9 years in Dead ones (P = 0.31) and they were born 18 years later (P = 0.0001). Pre-treatment serum total cholesterol (TC) was similar in Alive and Dead (20.2 ± 5.1 v 21.3 ± 4.4 mmol/l, P = 0.52) but on-treatment TC was lower in Alive than Dead (8.1 ± 2.8 v 14.5 ± 6.0 mmol/l, P = 0.0001) and CV adverse events were far less frequent (eg aortic stenosis, 33% v 77%, P = 0.02). CONCLUSIONS: The lower on-treatment TC and fewer CV adverse events in FH homozygotes still living reflect advances in apheresis and drug therapy since the 1990s. Further improvements in prognosis can be expected with the impending introduction of novel lipid-lowering agents.

Managing homozygous familial hypercholesterolaemia from cradle to grave.

OBJECTIVE: To describe the phenotypic and genotypic features and management of clinically homozygous familial hypercholesterolaemia (FH). METHODS: An analysis of current knowledge based on personal experience and published evidence. RESULTS: Atherosclerotic involvement of the aortic root is common in homozygous FH and can cause death before age 5. Receptor negative patients are at greatest risk, irrespective of whether they have identical mutations (homozygous) or dissimilar mutations (compound heterozygous). CONCLUSIONS: Lipoprotein apheresis combined with high dose statin and ezetimibe slows but does not arrest progression of atherosclerosis. Adjunctive use of novel compounds such as lomitapide and evolocumab should facilitate achieving the latter objective by enhancing the reduction in LDL cholesterol.

Lipoprotein apheresis in the management of familial hypercholesterolaemia: historical perspective and recent advances.

At present, lipoprotein apheresis, combined with high-dose statin and ezetimibe therapy, is the best available means of treating patients with homozygous and statin-refractory heterozygous familial hypercholesterolaemia (FH). However, the extent of cholesterol-lowering achieved is often insufficient to meet the targets set by current guidelines. The recent advent of three new classes of lipid-lowering agents provides new hope that the latter objective may now be achievable. These compounds act either by reducing low-density lipoprotein (LDL) production by inhibiting apolipoprotein B synthesis with an antisense oligonucleotide (mipomersen) or by inhibiting microsomal triglyceride transfer protein (lomitapide), or by enhancing LDL catabolism via monoclonal antibody-mediated inhibition of the activity of proprotein convertase subtilisin/kexin 9 (PCSK9) (evolocumab). Depending on the outcome of current trials, it seems likely that these compounds, used alone or combined with lipoprotein apheresis, will markedly improve the management of refractory FH.