Familial hypercholesterolemia (FH) is characterized by markedly increased LDL-cholesterol (LDL-C) and premature cardiovascular disease (CVD). LDL-C lowering is the cornerstone of therapy.
The aim of ...our study was to evaluate LDL-C target achievement and explore reasons for not reaching target in FH patients attending a public-sector lipid clinic at Groote Schuur Hospital in Cape Town, South Africa.
We reviewed clinical records of patients with genetically confirmed heterozygous FH (heFH) retrospectively. For patients seen after 2013, when new guidelines were published, we determined reasons for use of submaximal therapy.
Our study population consisted of 776 adult heFH patients. A substantial proportion (41%) of those younger than 50 years of age had already experienced a cardiovascular event. The mean (±SD) untreated and best achieved LDL-C values during follow up were 8.1 ± 2.1 and 4.0 ± 1.5 mmol/l, respectively. Despite a mean LDL-C reduction of 50%, only 140 (25%) achieved an LDL-C ≤ 3.0 mmol/l. Of the 164 participants with follow up after 2013, 42 did not reach LDL-C < 3.0 mmol/l and did not use maximal therapy (26%). The commonest reasons for not using maximum therapy were statin side-effects (n = 15, 36%) and acceptance by the patient (n = 9, 22%) or the physician (n = 8, 19%) of the control achieved.
The heFH population in Cape Town is characterized by high baseline LDL-C, a high prevalence of CVD at presentation and low rates of achieving an LDL-C target of 3.0 mmol/l.
•CVD risk is very high in the heFH population from Cape Town that we studied.•Despite a mean LDL-C reduction of 50% only 25% achieved a LDL-C < 3,0 mmol/l.•Early identification and aggressive treatment of FH is important.•PCSK9 inhibitors should be prescribed based on risk and distance from LDL-C target.
Familial hypercholesterolaemia (FH) is the commonest monogenic disorder that accelerates atherosclerotic cardiovascular disease. We compared and contrasted the characteristics of patients from three ...specialist centres in the southern hemisphere.
Adult index-cases with molecularly diagnosed heterozygous FH attending specialist lipid centres in Cape Town, Perth and São Paulo were studied. Myocardial infarction, revascularisation, hypertension, diabetes, smoking and lipid-lowering treatment were recorded at the time of diagnosis and compared across the three centres.
The spectrum of genetic variants causative of FH was significantly different in patients attending the centres in South Africa compared with Australia and Brazil. Hypertension and diabetes were more prevalent in Brazilian and Australian patients, than in South African patients, but the frequency of smoking was significantly greater in South Africa than the other two centres (p<0.01). Age, male sex and smoking were significant independent predictors of coronary artery disease (CAD) in all three countries (p<0.05).
Patients with FH in three specialist centres in the southern hemisphere exhibit a high prevalence of non-cholesterol cardiovascular disease risk factors. Older age, male sex and smoking were more common among subjects with CAD. In all three countries, there should be vigorous programmes for the control of risk factors beyond good control of hypercholesterolaemia among patients with FH. Promotion of a healthy lifestyle, especially anti-smoking advice, is of paramount importance.
•Heterozygous familial hypercholesterolaemia (FH) is the commonest monogenic lipid disorder that accelerates atherosclerotic cardiovascular disease.•Despite differences in genetic variants causing FH, patients attending lipid specialist centres in South Africa, Australia and Brazil have a high prevalence of non-cholesterol risk factors that impact on the risk of coronary artery disease (CAD).•In all three specialist centres, age at diagnosis and current or former smoking were consistent predictors of CAD. This underscores the importance of early treatment of FH patients, as well as counselling against smoking.
A data deficit in shallow groundwater monitoring in Africa exists despite one million handpumps being used by 200 million people every day. Recent advances with “smart handpumps” have provided ...accelerometry data sent automatically by SMS from transmitters inserted in handles to estimate hourly water usage. Exploiting the high-frequency “noise” in handpump accelerometry data, we model high-rate wave forms using robust machine learning techniques sensitive to the subtle interaction between pumping action and groundwater depth. We compare three methods for representing accelerometry data (wavelets, splines, Gaussian processes) with two systems for estimating groundwater depth (support vector regression, Gaussian process regression), and apply three systems to evaluate the results (held-out periods, held-out recordings, balanced datasets). Results indicate that the method using splines and support vector regression provides the lowest overall errors. We discuss further testing and the potential of using Africa's accidental infrastructure to harmonise groundwater monitoring systems with rural water-security goals.
•A data deficit exists in shallow groundwater monitoring in Africa.•Our “smart handpump” has low-cost accelerometers mounted in the handle.•We show that machine learning methods applied to the accelerometry can estimate aquifer depth.•We demonstrate that we can use the “accidental infrastructure” of handpumps for estimating groundwater levels.
Familial Dysbetalipoproteinemia (FD) is the second most common monogenic dyslipidemia and is associated with a very high cardiovascular risk due to cholesterol‐enriched remnant lipoproteins. FD is ...usually caused by a recessively inherited variant in the APOE gene (ε2ε2), but variants with dominant inheritance have also been described. The typical dysbetalipoproteinemia phenotype has a delayed onset and requires a metabolic hit. Therefore, the diagnosis of FD should be made by demonstrating both the genotype and dysbetalipoproteinemia phenotype. Next Generation Sequencing is becoming more widely available and can reveal variants in the APOE gene for which the relation with FD is unknown or uncertain. In this article, two approaches are presented to ascertain the relationship of a new variant in the APOE gene with FD. The comprehensive approach consists of determining the pathogenicity of the variant and its causal relationship with FD by confirming a dysbetalipoproteinemia phenotype, and performing in vitro functional tests and, optionally, in vivo postprandial clearance studies. When this is not feasible, a second, pragmatic approach within reach of clinical practice can be followed for individual patients to make decisions on treatment, follow‐up, and family counseling.
There are now ample data that demonstrate that inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) can safely lower LDL cholesterol synergistically with statins. Considering that ...PCSK9 was first identified less than a decade ago, the last few years have shown rapid and remarkable advancements in our understanding and knowledge of the structure and function of PCSK9.
Therapeutic developments have not lagged far behind with some monoclonal antibodies currently entering phase III trials. Of the many approaches to PCSK9 inhibition, these compounds are the furthest advanced in their clinical development while small molecule oral inhibitors seem a distant prospect.
This review summarizes the discovery and history of PCSK9 and in particular its mode of action as an inhibitor of the LDL receptor. It also recapitulates key studies that have demonstrated the potential of inhibiting PCSK9 to further decrease LDL-cholesterol levels safely and synergistically with statins. Finally, we review the strategies that are currently in development to inhibit PCSK9, with a special emphasis on the spectacular results from recent phase-I and phase-II clinical trials.
•For this study data from a randomized trial performed in 28 patients with FD were used.•Friedewald, Martin-Hopkins, direct assay and gels to determine LDL-C were compared to UC.•All methods over- or ...underestimated LDL-C concentrations compared to UC.•UC probably overestimates LDL-C concentrations as well.•Non-HDL-C measured by standard assays performed well compared to non-HDL-C by UC.
To compare LDL-C concentrations using the Friedewald formula, the Martin-Hopkins formula, a direct assay and polyacrylamide gradient gel electrophoresis (PGGE) to the reference standard density gradient ultracentrifugation in patients with Familial Dysbetalipoproteinemia (FD) patients. We also compared non-HDL-cholesterol concentrations by two methods.
For this study data from 28 patients with genetically confirmed FD from the placebo arm of the EVOLVE-FD trial were used. Four different methods for determining LDL-C were compared with ultracentrifugation. Non-HDL-C was measured with standard assays and compared to ultracentrifugation. Correlation coefficients and Bland-Altman plots were used to compare the methods.
Mean age of the 28 FD patients was 62 ± 9 years, 43 % were female and 93 % had an ɛ2ɛ2 genotype. LDL-C determined by Friedewald (R2 = 0.62, p <0.01), Martin-Hopkins (R2 = 0.50, p = 0.01) and the direct assay (R2 = 0.41, p = 0.03) correlated with density gradient ultracentrifugation. However, Bland-Altman plots showed considerable over- or underestimation by the four methods compared to ultracentrifugation. Non-HDL-C showed good correlation and agreement.
In patients with FD, all four methods investigated over- or underestimated LDL-C concentrations compared with ultracentrifugation. In contrast, standard non-HDL-C assays performed well, emphasizing the use of non-HDL-C in patients with FD.
Background and Aim: The methionine choline‐deficient (MCD) diet leads to steatohepatitis in rodents. The aim of the present study was to investigate species, strain and sex differences in this ...nutritional model of non‐alcoholic steatohepatitis (NASH).
Methods: Male and female Wistar, Long–Evans and Sprague–Dawley rats, and C57/BL6 mice (n = 6 per group) were fed a MCD diet for 4 weeks. Control groups received an identical diet supplemented with choline bitartrate (0.2% w/w) and methionine (0.3% w/w). Liver pathology (steatosis and inflammation) and ultrastructure, liver lipid profile (total lipids, triglycerides, lipid peroxidation products), liver : body mass ratios and serum alanine aminotransferase (ALT) levels were compared between these groups.
Results: The MCD diet‐fed male rats developed greater steatosis (P < 0.001), had higher liver lipid content (P < 0.05) and had higher serum ALT levels (P < 0.005) than did female rats. Wistar rats (both sexes) had higher liver lipid levels (P < 0.05), serum ALT levels (P < 0.05), and liver mass : body mass ratios (P < 0.025) than did Long–Evans and Sprague–Dawley rats. In female groups, Wistar rats showed greater fatty change than did the other two strains (P < 0.05). All rats fed the MCD diet developed hepatic steatosis, but necrosis and inflammation were minor features and fibrosis was absent. Compared with Wistar rats, male C57/BL6 mice showed a marked increase in inflammatory foci (P < 0.001), end products of lipid peroxidation (free thiobarbituric acid reactive substances) (P < 0.005), and mitochondrial injury, while showing less steatosis (P < 0.005), lower hepatic triglyceride levels, (P < 0.005) and lower early lipid peroxidation products (conjugated dienes and lipid hydroperoxides; P < 0.005 and P < 0.01, respectively).
Conclusions: The Wistar strain and the male sex are associated with the greatest degree of steatosis in rats subjected to the MCD diet. Of the groups studied, male C57/BL6 mice develop the most inflammation and necrosis, lipid peroxidation, and ultrastructural injury, and best approximate the histological features of NASH.
Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic ...distribution are lacking. Furthermore, no randomized treatment study in this population has been reported.
We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001).
PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients.
URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.
OBJECTIVE:Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, ...low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel PCSK9 variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays.
APPROACH AND RESULTS:Patients with clinically diagnosed FH underwent genetic analysis of LDLR, and if negative, sequential testing of APOB and PCSK9. We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P<0.001). In vitro studies demonstrated the pathogenicity of the G516V variant.
CONCLUSIONS:In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in PCSK9. Pathogenicity is established beyond doubt for the G516V variant.
Clearance of triglyceride-rich lipoproteins (TRLs) is mediated by several receptors, including heparan sulfate proteoglycans (HSPGs). Sulfate glucosamine-6-O-endosulfatase-2 is a gene related to the ...regulation of HSPG. A variant in this gene, rs2281279, has been shown to be associated with triglycerides and insulin resistance.
To determine the relationship between rs2281279, metabolic parameters and vascular events, and type 2 diabetes mellitus (T2DM) in patients at high cardiovascular risk and whether
genotype modifies this relationship.
Patients (
= 4386) at high cardiovascular risk from the Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease study were stratified according to their imputed rs2281279 genotype: AA (
= 2438), AG (
= 1642) and GG (
= 306). Effects of rs2281279 on metabolic parameters, vascular events and T2DM were analyzed with linear regression and Cox models.
There was no relationship between imputed rs2281279 genotype and triglycerides, non-high-density lipoprotein (HDL)-cholesterol, insulin and quantitative insulin sensitivity check index. During a median follow-up of 11.8 (IQR, 9.3-15.5) years, 1026 cardiovascular events and 320 limb events occurred. The presence of the G allele in rs2281279 did not affect the risk of vascular events hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.94-1.14 or limb events (HR, 0.92; 95% CI, 0.77-1.10). The presence of the G allele in rs2281279 did not affect the risk of T2DM (HR, 1.09; 95% CI, 0.94-1.27). The presence of the minor G allele of rs2281279 was associated with a beneficial risk profile in ε2ε2 patients, but not in ε3ε3 patients.
Imputed rs2281279 genotype is not associated with metabolic parameters and does not increase the risk of vascular events or T2DM in patients at high risk for cardiovascular disease.
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