Ten years of lipoprotein apheresis for familial hypercholesterolemia in Malaysia: A creative approach by a cardiologist in a developing country.

BACKGROUND: Familial hypercholesterolemia (FH) leads to premature coronary artery disease and aortic stenosis, with undertreated severe forms causing death at a young age. Lipoprotein apheresis (LA) is often required for lowering low-density lipoprotein cholesterol levels in severe FH. OBJECTIVES: The objective of this study was to present the first experiences with LA in Malaysia, between 2004 and 2014. METHODS: We retrospectively collected data from patient records to assess the effectiveness, adverse effects, patient quality of life, and costs associated with an LA service for genetically confirmed homozygous and heterozygous FH. RESULTS: We treated 13 women and 2 men aged 6 to 59 years, 10 with homozygous and 5 with heterozygous FH, all on maximally tolerated cholesterol-lowering drug therapy, for a total of 65 patient-years. Acute lowering of low-density lipoprotein cholesterol post apheresis was 56.3 ± 7.2%, with time-averaged mean lowering of 34.9 ± 13.9%. No patients experienced any cardiovascular events during the period of receiving LA. Patients receiving LA experienced few side effects and enjoyed reasonable quality of life, but inability to continue treatment was frequent because of cost. CONCLUSION: LA for severe FH can be delivered effectively in the short term in developing nations, but costs are a major barrier to sustaining this mode of treatment for this high-risk group of patients. New drug therapies for FH, such as the proprotein convertase subtilisin/kexin type 9 inhibitors, microsomal triglyceride transfer protein inhibitors, and apolipoprotein-B100 antisense oligonucleotides may allow improved care for these patients, but costs and long-term safety remain as issues to be addressed.

Translational Research for Improving the Care of Familial Hypercholesterolemia: The "Ten Countries Study" and Beyond.

Familial hypercholesterolemia (FH) is the most common and serious form of inherited hyperlipidaemia. Dominantly inherited with high penetrance, untreated FH leads to premature death from coronary artery disease due to accelerated atherosclerosis from birth. Despite its importance, there is still a major shortfall in awareness, detection and treatment of FH worldwide. International models of care for FH have recently been published, but their effective implementation requires the garnering of more knowledge about the condition. The "Ten Countries Study" aims to investigate diagnostic, epidemiological and service aspects, as well as physician practices and patient experiences of FH in several countries in the Asia-Pacific Region and the Southern Hemisphere. Five observational studies are being undertaken that will systematically investigate the following aspects of FH: the phenotypic predictors of low-density lipoprotein receptor mutations, the point prevalence in available community populations, current knowledge and clinical practices among primary care physicians, availability and utilisation of services and facilities, and patient perceptions and personal experiences of the condition. The information gathered will inform better clinical practice and will enable the development of country-specific models of care for FH.

Lipid-lowering treatment in hypercholesterolaemic patients: the CEPHEUS Pan-Asian survey.

BACKGROUND: Treatment of hypercholesterolaemia in Asia is rarely evaluated on a large scale, and data on treatment outcome are scarce. The Pan-Asian CEPHEUS study aimed to assess low-density lipoprotein cholesterol (LDL-C) goal attainment among patients on lipid-lowering therapy. METHODS: This survey was conducted in eight Asian countries. Hypercholesterolaemic patients aged ≥18 years who had been on lipid-lowering treatment for ≥3 months (stable medication for ≥6 weeks) were recruited, and lipid concentrations were measured. Demographic and other clinically relevant information were collected, and the cardiovascular risk of each patient was determined. Definitions and criteria set by the updated 2004 National Cholesterol Education Program guidelines were applied. RESULTS: In this survey, 501 physicians enrolled 8064 patients, of whom 7281 were included in the final analysis. The mean age was 61.0 years, 44.4% were female, and 85.1% were on statin monotherapy. LDL-C goal attainment was reported in 49.1% of patients overall, including 51.2% of primary and 48.7% of secondary prevention patients, and 36.6% of patients with familial hypercholesterolaemia. The LDL-C goal was attained in 75.4% of moderate risk, 55.4% of high risk, and only 34.9% of very high-risk patients. Goal attainment was directly related to age and inversely related to cardiovascular risk and baseline LDL-C. CONCLUSION: A large proportion of Asian hypercholesterolaemic patients on lipid-lowering drugs are not at recommended LDL-C levels and remain at risk for cardiovascular disease. Given the proven efficacy of lipid-lowering drugs in the reduction of LDL-C, there is room for further optimization of treatments to maximize benefits and improve outcomes.

Functional analysis of the synonymous R385R mutation in the low-density lipoprotein receptor gene.

Familial hypercholesterolemia is caused by mutations in the low-density lipoprotein receptor (LDLR) gene. The synonymous mutation R385R has been shown to introduce a cryptic splice site in exon 9. The aims of this study were to establish to what extent the cryptic splice site is selected ahead of the normal splice site and to determine if the aberrant transcript is degraded by nonsense-mediated mRNA decay. The relative amount of the aberrant transcript was determined by real-time PCR and found to vary from 25% to 45% in heterozygous familial hypercholesterolemia individuals. Epstein-Barr virus-transformed lymphocytes were established from one heterozygous patient, and treatment of these cells with cycloheximide increased the amount of aberrant transcript, indicating that the aberrant transcripts are degraded by nonsense-mediated mRNA decay. Cloning of reverse transcriptase-PCR products from one of the heterozygous patients and introduction of the R385R mutation into a minigene reporter construct revealed an almost exclusive use of the cryptic splice site in the mutated allele. Thus, the synonymous mutation R385R converts the mutated allele to a null allele unable to produce functional mRNA.

Lipoprotein lipase gene analyses in one Turkish family and three different Chinese families with severe hypertriglyceridaemia: one novel and several established mutations.

Lipoprotein lipase (LPL, triacylglycerol acylhydrolase; EC 3.1.1.3) deficiency (OMIM 238600) is an autosomal recessive inherited condition caused by mutations in the LPL gene, either in a homozygous or in a compound heterozygous state, leading to loss of lipolytic activity and resulting in severe hypertriglyceridaemia and subsequent risk for developing pancreatitis. Numerous LPL gene mutations leading to loss of catalytic function have been described. In this present study, we describe full clinical, biochemical and molecular analyses of severe hypertriglyceridaemic individuals in one Turkish and three Chinese families. We established one novel mutation (delCT1312-1313), a new combination of mutations (S193R and I194T) and four previously reported mutations (L252R, L252V, S193R and I194T) of the LPL gene and report phenotypes for these and four previously described mutations. Finally, we show that two patients homozygous for the LPL gene delCT1312-1313 mutations are characterized by absence of LPL activity that coincides with absence of LPL protein.