Hypercholesterolemia: Wierzbicki AS

Wierzbicki AS, Humphries SE, Minhas R, Anonymous00232. · St Thomas' Hospital, London SE1 7EH. · BMJ. · Pubmed #18753174 No free full text.

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Viljoen A, Wierzbicki AS. · No affiliation provided · Int J Clin Pract. · Pubmed #18324945 No free full text.

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Wierzbicki AS. · No affiliation provided · Br J Hosp Med (Lond). · Pubmed #17554938 No free full text.

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Wierzbicki AS. · No affiliation provided · Int J Clin Pract. · Pubmed #14627172 No free full text.

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Wierzbicki AS. · No affiliation provided · Int J Clin Pract. · Pubmed #11321864 No free full text.

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Wierzbicki AS, Graham CA, Young IS, Nicholls DP. · St. Thomas' Hospital, London SE 1 7EH, UK. · Curr Vasc Pharmacol. · Pubmed #18220935 No free full text.

Abstract: Familial combined hyperlipidaemia (FCH) was identified in early genetic studies of populations as a dominant condition associated with mixed hyperlipidaemia and early onset coronary heart disease. Later studies extended the phenotype and noted that this genetic hyperlipidaemia was sensitive to environmental effects. This article reviews the definitions, animal models and genetics of FCH. In contrast to familial hypercholesterolaemia, which is caused by mutations in a limited number of affected genes, the genetics of FCH have remained obscure and very few definite candidate genes have been identified. A strong role for the apoA-I, A-IV, A-V, C-III cluster on chromosome 11 was identified early on and multiple associations have been found to hyperlipidaemia in this region and more strongly to adjacent sections of the chromosome. More recently quantitative trait mapping has identified a number of candidate genes including upstream transcription factor -1 (USF-1) on 1 q21 and CD-36 on chromosome 4. Of these the strongest evidence, based on 4 analyses, links the lipid components of FCH to intronic variants in the USF-1 gene on chromosome 1q21-23. Unfortunately USF-1 yet fails to show clear associations with diabetes and the metabolic syndrome which co-map to this region and are also associated with mixed hyperlipidaemia. Large scale validation of USF-1 variants in other populations is still awaited. It is likely that FCH is a heterogeneous condition, that is subject to wide-scale environmental confounding from common traits such as obesity and the metabolic syndrome, and that the resolution of its genetics is going to prove a severe challenge.

Liberopoulos EN, Daskalopoulou SS, Mikhailidis DP, Wierzbicki AS, Elisaf MS. · Department of Internal Medicine, Medical School, University of Ioannina, Greece. · Curr Med Res Opin. · Pubmed #15801994 No free full text.

Abstract: BACKGROUND: Statin therapy has been shown to significantly decrease vascular events and overall mortality in primary and secondary prevention trials. This review considers the pharmacology, nonlipid-lowering effects and clinical trial evidence of fluvastatin based on a survey of PubMed entries. FINDINGS: Recent clinical data show that treatment with fluvastatin is associated with a variety of benefits in different high-risk populations along with a good safety profile. Fluvastatin exerts non-lipid lowering-associated pleiotropic effects in both clinical and experimental studies. Furthermore, an extended-release formulation of fluvastatin with a favourable pharmacokinetic profile is available. CONCLUSION: Treatment with fluvastatin offers a convenient, safe and evidence-based approach to managing dyslipidaemias and preventing vascular events.

Wierzbicki AS. · St Thomas' Hospital Campus, London, UK. · Int J Clin Pract. · Pubmed #15605675 No free full text.

Abstract: Lipid-lowering is established as proven intervention to reduce atherosclerosis and its complications. This article summarises novel developments in the lipid-altering therapies under development. It also discusses other therapeutic targets, such as squalene synthase, microsomal transfer protein, acyl-cholesterol acyl transferase, cholesterol ester transfer protein, peroxosimal proliferator-activating receptors and lipoprotein (a), for which compounds have been developed and have at least reached trials in animal models. Lipid-altering drugs are likely to prove a fast-developing area for novel treatments, as possible synergies exist between new and established compounds for the treatment of atherosclerosis.

Wierzbicki AS, Poston R, Ferro A. · Department of Chemical Pathology, GKT School of Medicine, King's College London, London, UK. · Pharmacol Ther. · Pubmed #12804701 No free full text.

Abstract: The 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, more commonly known as statins, are a class of drug widely used for the treatment of hypercholesterolaemia in patients with established cardiovascular disease as well as those at high risk of developing atherosclerosis. Their predominant action is to reduce circulating levels of low-density lipoprotein (LDL) cholesterol; to a smaller degree, they also increase high-density lipoprotein (HDL) cholesterol and reduce triglyceride concentrations. In recent years, however, there has been an increasing body of evidence that their effects on lipid profile cannot fully account for their cardiovascular protective actions: their beneficial effects are too rapid to be easily explained by their relatively slow effects on atherogenesis and too large to be accounted for by their relatively small effects on plaque regression. Experimental models have revealed that statins exert a variety of other cardiovascular effects, which would be predicted to be of clinical benefit: they possess anti-inflammatory properties, as evidenced by their ability to reduce the accumulation of inflammatory cells in atherosclerotic plaques; they inhibit vascular smooth muscle cell proliferation, a key event in atherogenesis; they inhibit platelet function, thereby limiting both atherosclerosis and superadded thrombosis; and they improve vascular endothelial function, largely through augmentation of nitric oxide (NO) generation. The relative importance of the lipid- and non-lipid-related effects of the statins in the clinical situation remains the subject of much continuing research.

Nair DR, Wierzbicki AS, Mikhailidis DP. · Department of Molecular Pathology and Clinical Biochemistry, Royal Free and University College Medical School, Royal Free Campus, London NW3 2QG, England. · J R Soc Promot Health. · Pubmed #11467215 No free full text.

Abstract: There is convincing epidemiological evidence indicating that the serum levels of high density lipoprotein (HDL) cholesterol are inversely related to the risk of vascular events. Similarly, intervention trials, involving healthy populations and patients with coronary heart disease (CHD), have shown that raising the serum levels of HDL is associated with a significant decrease in the risk of vascular events. It follows that serum HDL levels must be considered when assessing risk and setting therapeutic goals. Some of the currently available national treatment guidelines reflect this view. The present review considers the place of serum HDL measurement in the prevention of vascular events.

Wierzbicki AS. · Department of Chemical Pathology, St. Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom. · Expert Opin Pharmacother. · Pubmed #11336625 No free full text.

Abstract: Atorvastatin (Lipitor, Pfizer) is a safe and effective 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin). It is the most potent currently available statin in terms of lowering low-density lipoprotein (LDL) and total cholesterol levels. It was the first statin shown to lower triglycerides in patients with isolated hypertriglyceridaemia. It has a good safety profile. In common with other statins, it has non-lipid-lowering effects including improving endothelial function, antiproliferative actions on smooth muscle and reducing platelet aggregation. It also has anti-inflammatory effects and may reduce plasma glucose levels. Clinical trial evidence with this statin is currently limited. It did slightly reduce events in the AVERT trial comparing patients receiving coronary angioplasty with those receiving high-dose atorvastatin therapy and in the MIRACL study reduced ischemia in patients with acute coronary syndromes. Other end point trials are in progress.

Wierzbicki AS, Doherty E, Lumb PJ, Chik G, Crook MA. · Department of Chemical Pathology, St. Thomas' Hospital, London, UK. · Curr Med Res Opin. · Pubmed #15811200 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy of the cholesterol absorption inhibitor ezetimibe in patients with refractory familial hyperlipidaemia or intolerant to statin therapy. METHODS: This prospective study assessed the safety and efficacy of ezetimibe in 200 patients with refractory familial hyperlipidaemias not achieving a low-density-lipoprotein (LDL) cholesterol < 3 cholesterol < 3 mmol/L (116 mg/dL) including 22% intolerant to all statin therapy, many consuming intolerant to all statin therapy, many consuming sterol-containing products. RESULTS : Ezetimibe monotherapy resulted in 7% and 11% reductions in LDL-cholesterol and apolipoprotein B respectively. Ezetimibe-statin combination therapy reduced LDL-cholesterol by an additional 11 +/- 27% and apolipoprotein B by 11 (+79 to -18)%. There was a similar response between various sub-groups but a wide variation within groups with the greatest effect seen in patients groups with the greatest effect seen in patients under-responding to statins. The number of patients achieving the LDL-C target of 3 mmol/L rose from 5.5% to 18%. Non-significant effects included a 5 (+78 to -470)% reduction in triglycerides, 8 +/- 36% increment in HDL-cholesterol, 21 (+35 to -82)% reduction in C-reactive protein and a 1 (+20 to -50)% increase in alanine transaminase. No effects were seen on creatinine, creatine kinase, or insulin resistance. Fourteen patients (7%) discontinued ezetimibe: seven due to gastrointestinal side-effects, one patient developed an ezetimibe-induced hypercholesterolaemia (x 1.5), one developed ezetimibe-induced hypertriglyceridaemia (x 7) and five discontinued for other reasons. CONCLUSION: Ezetimibe is a useful addition to statins in patients with familial hyperlipidaemias but shows a highly variable response profile.

Marteau T, Senior V, Humphries SE, Bobrow M, Cranston T, Crook MA, Day L, Fernandez M, Horne R, Iversen A, Jackson Z, Lynas J, Middleton-Price H, Savine R, Sikorski J, Watson M, Weinman J, Wierzbicki AS, Wray R, Anonymous00031. · Psychology & Genetics Research Group, King's College London, London, United Kingdom. · Am J Med Genet A. · Pubmed #15216550 No free full text.

Abstract: This trial tests the hypothesis that confirming a clinical diagnosis of familial hypercholesterolemia (FH) by finding a genetic mutation reduces patients' perceptions of control over the disease and adherence to risk-reducing behaviors. Three hundred forty-one families, comprising 341 hypercholesterolemia probands and 128 adult relatives, were randomized to one of two groups: (a) routine clinical diagnosis; (b) routine clinical diagnosis plus genetic testing (mutation searching in probands and direct gene testing in relatives). The main outcome measures were perceptions of control over hypercholesterolemia, adherence to cholesterol-lowering medication, diet, physical activity, and smoking. There was no support for the main hypothesis: finding a mutation had no impact on perceived control or adherence to risk-reducing behavior (all P-values > 0.10). While all groups believed that lowering cholesterol was an effective way of reducing the risk of a heart attack, participants in whom a mutation was found believed less strongly in the efficacy of diet in reducing their cholesterol level (P = 0.02 at 6 months) and showed a trend in believing more strongly in the efficacy of cholesterol-lowering medication (P = 0.06 at 6 months). In conclusion, finding a mutation to confirm a clinical diagnosis of FH in a previously aware population does not reduce perceptions of control or adherence to risk-reducing behaviors. The pattern of findings leads to the new hypothesis that genetic testing does not affect the extent to which people feel they have control over a condition, but does affect their perceptions of how control is most effectively achieved. Further work is needed to determine whether similar results will be obtained in populations with little previous awareness of their risks.

Wierzbicki AS, Lumb PJ, Chik G. · Department of Chemical Pathology, St Thomas' Hospital, London, UK. · Int J Clin Pract. · Pubmed #11777291 No free full text.

Abstract: High-dose preparations of simvastatin and atorvastatin have recently become available to treat resistant hypercholesterolaemia aggressively, but few studies have compared these two agents. This study compared the efficacy of simvastatin 80 mg and 120 mg in 22 patients with severe familial hypercholesterolaemia over a three-month period using an open label format. Simvastatin 120 mg was reasonably well tolerated and delivered a further 8% reduction in LDL over 80 mg, giving a total reduction of 55 +/- 13%, while further decreasing triglycerides (18%) and continuing to raise HDL (13%) further than the 80 mg dose. However, transient adverse changes were noted in both lipoprotein (a) and fibrinogen and 20% of patients were unable to tolerate the higher dose. One late case of rhabdomyolysis was observed, suggesting patients on the 120 mg dose require continued regular review.

Wierzbicki AS, Lumb PJ, Chik G, Crook MA. · Department of Chemical Pathology, King's College London, Guy's, King's & St. Thomas' Medical School, United Kingdom. · Am J Cardiol. · Pubmed #11165973 No free full text.

Abstract: The clinical and biochemical determinants of the fibrinogen response to simvastatin or atorvastatin therapy were assessed in 130 patients with severe polygenic or familial hypercholesterolemia treated in a randomized open-trial format design. Hyperfibrinogenemia was associated with atorvastatin, baseline fibrinogen, and initial concentration and change in concentration of apolipoprotein B or low-density lipoprotein cholesterol.

Wierzbicki AS, Lumb PJ, Chik G, Crook MA. · Department of Chemical Pathology, King's College London, Guy's, King's & St Thomas' Medical School, United Kingdom. · Am J Cardiol. · Pubmed #11009276 No free full text.

Abstract: The clinical and biochemical determinants of high-density lipoprotein (HDL) and triglyceride response to simvastatin and atorvastatin were assessed in 150 patients with severe hyperlipidemia treated in a randomized open-trial format design. Triglyceride reduction was only dependent on HDL:apolipoprotein A1, change in apolipoprotein B, and dose response, whereas an increase in HDL was dependent on initial LDL, change in LDL or dose response, and therapy with simvastatin.

Wierzbicki AS, Lumb PJ, Chik G, Crook MA. · Department of Chemical Pathology, St Thomas' Hospital, London. · Int J Clin Pract. · Pubmed #10692755 No free full text.

Abstract: This study compared the efficacy of simvastatin 80 mg and atorvastatin 80 mg in the treatment of 26 patients with familial hypercholesterolaemia over 12 weeks using an open crossover trial format. Both, similarly, reduced LDL by 47 +/- 13% and 43 +/- 16% and median triglycerides by 22% and 27% respectively. However, atorvastatin reduced HDL by 2 +/- 24% compared with 8 +/- 30% increase with simvastatin (p = 0.05) affecting the LDL:HDL ratio achieved (4.478 +/- 1.56 vs 3.74 +/- 0.93, p = 0.001). Atorvastatin raised median fibrinogen by 15% compared with a non-significant 5% increase with simvastatin (p = 0.05). Simvastatin reduced lipoprotein (a) by a median 20% compared with baseline (p = 0.05) compared with 5% for atorvastatin. Side-effects, mostly gastrointestinal, were seen in four patients (16%) with atorvastatin compared with one case of myalgia with simvastatin (4%). We conclude both drugs are equally effective in LDL reduction but that simvastatin is superior in raising HDL and causes fewer side-effects. These results require confirmation in larger studies.

Wierzbicki AS. · Department of Chemical Pathology, St. Thomas' Hospital, London, UK. · Int J Clin Pract. · Pubmed #18822020 No free full text.

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Gray J, Jaiyeola A, Whiting M, Modell M, Wierzbicki AS. · Wandsworth Primary Care Research Group, Bolingbroke Hospital, London, UK. · Heart. · Pubmed #17575326 No free full text.

Abstract: BACKGROUND: Familial hypercholesterolaemia (FH) is associated with highly raised low-density lipoprotein-cholesterol and causes early-onset cardiovascular disease. Its autosomal dominant inheritance allows family cascade screening to be performed once an index case has been identified. However, the vast majority of people with FH in the United Kingdom have not been identified, and there is no national screening programme. OBJECTIVE: To assess the utility of combined computer- and notes-based searches in identifying index cases of FH in primary care, and to uncover the degree of case overlap with secondary care. METHODS: Four computer searches were conducted in one South London practice with a registered population of 12,100 patients. Selected notes were reviewed by a general practitioner and consultant lipidologist to give a Dutch score for the probability of FH. RESULTS: 402/12,100 (3.3%) patients had a Dutch score high enough to require a notes review. Twelve cases of definite FH were found, of whom two were unknown to the practice. Eight probable cases were found, seven of whom were previously unknown. 2/12 (17%) definite cases and 4/8 (50%) probable cases were unknown to a secondary care lipid clinic. 216/402 (54%) patients scored as possible cases. After specialist review 47/216 (21.8%) patients would merit recalling for a detailed family history and xanthoma examination. CONCLUSIONS: There are both diagnosed and undiagnosed cases of FH in primary care not known to secondary care. Significant potential exists to identify new cases of FH in primary care who could act as new index cases for a family screening programme.

Humphries SE, Cranston T, Allen M, Middleton-Price H, Fernandez MC, Senior V, Hawe E, Iversen A, Wray R, Crook MA, Wierzbicki AS. · Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, Rayne Building, 5 University Street, London WC1E 6JJ, UK. · J Mol Med. · Pubmed #16389549 No free full text.

Abstract: As part of a randomised trial [Genetic Risk Assessment for Familial Hypercholesterolaemia (FH) Trial] of the psychological consequences of DNA-based and non-DNA-based diagnosis of FH, 338 probands with a clinical diagnosis of FH (46% with tendon xanthomas) were recruited. In the DNA-based testing arm (245 probands), using single-strand conformation polymorphism of all exons of the low-density lipoprotein receptor (LDLR) gene, 48 different pathogenic mutations were found in 62 probands (25%), while 7 (2.9%) of the patients had the R3500Q mutation in the apolipoprotein B (APOB) gene. Compared to those with no detected mutation, mean untreated cholesterol levels in those with the APOB mutation were similar, while in those with an LDLR mutation levels were significantly higher (None=9.15+/-1.62 vs LDLR=9.13+/-1.16 vs APOB=10.26+/-2.07 mmol/l p<0.001, respectively). Thirty seven percent of the detected mutations were in exon 3/4 of LDLR, and this group had significantly higher untreated cholesterol than those with other LDLR mutations (11.71+/-2.39 mmol/l vs 9.88+/-2.44 mmol/l, p=0.03), and more evidence of coronary disease compared to those with other LDLR or APOB mutations (36 vs 13% p=0.04). Of the probands with a detected mutation, 54 first-degree relatives were identified, of whom 27 (50%) had a mutation. Of these, 18 had untreated cholesterol above the 95th percentile for their age and gender, but there was overlap with levels in the non-carrier relatives such that 12% of subjects would have been incorrectly diagnosed on lipid levels alone. In the non-DNA-based testing arm (82 probands) only 19 of the 74 relatives identified had untreated cholesterol above the 95th percentile for their age and gender, which was significantly lower (p<0.0005) than the 50% expected for monogenic inheritance. These data confirm the genetic heterogeneity of LDLR mutations in the UK and the deleterious effect of mutations in exon 3 or 4 of LDLR on receptor function, lipids and severity of coronary heart disease. In patients with a clinical diagnosis of FH but no detectable mutation, there is weaker evidence for a monogenic cause compared with relatives of probands with LDLR mutations. This supports the usefulness of DNA testing to confirm diagnosis of FH for the treatment of hyperlipidaemia and for further cascade screening.

Mikhailidis DP, Wierzbicki AS, Daskalopoulou SS, Al-Saady N, Griffiths H, Hamilton G, Monkman D, Patel V, Pittard J, Schachter M. · Dept Clinical Biochemistry (Vascular Disease Prevention Clinics) Royal Free Hospital, Royal Free & University College Medical School, London, UK. · Curr Med Res Opin. · Pubmed #15969896 No free full text.

Abstract: There is no doubt that lowering serum cholesterol levels reduces the risk of major coronary events. This evidence has led treatment guidelines to set progressively lower targets for low density lipoprotein cholesterol (LDL-C). However, despite widespread use of statins, substantial numbers of patients do not achieve the LDL-C goals. Using higher doses of statins in an attempt to achieve these targets may increase the risk of serious adverse effects. Furthermore, the use of combination therapy with agents such as bile acid sequestrants, niacin and fibrates has been limited by increased potential for side effects, drug interactions and poor compliance. Ezetimibe, a selective cholesterol transport inhibitor, reduces the intestinal uptake of cholesterol without affecting absorption of triglycerides or fat-soluble vitamins. In clinical studies, ezetimibe 10 mg, in combination with statins or as monotherapy, was well tolerated and reduced LDL-C by 34-53% and 17-18%, respectively. The available evidence for ezetimibe is reviewed. The role of ezetimibe in increasing the proportion of patients attaining LDL-C treatment goals is discussed.

Doherty E, Lumb PJ, Chik G, Wierzbicki AS. · Department of Diabetes, St. Thomas' Hospital, London, UK. · Int J Clin Pract Suppl. · Pubmed #15875607 No free full text.

Abstract: Ezetimibe is intestinally active cholesterol absorption inhibitor used to reduce low-density lipoprotein-cholesterol levels. This case report describes a novel side effect with this agent: ezetimibe-induced hyperlipidaemia in a patient with statin intolerance and familial combined hyperlipidaemia. Ezetimibe therapy induced an asymptomatic 770% increase in triglycerides (TGs) (3.51-27.1 mmol/l) and a 190% increase in total cholesterol (9.8-18.5 mmol/ 1) secondary to an increase (4.6-25.9 micromol/l; 560%) in hepatic cholesterol (lathosterol) synthesis. This lipid profile resolved 9 months after cessation of ezetimibe therapy. This report shows that ezetimibe may have long-lasting effects in man far exceeding its plasma half-life and that ezetimibe monotherapy can induce a large increase in hepatocyte very-low-density lipoprotein synthesis in rare individuals with a consequent mixed hyperlipidaemia or possibly hypercholesterolaemia depending on the metabolism and clearance of TG-rich lipoproteins.

Suryanarayanan S, Wierzbicki AS, Carr R, Ritter JM. · St Thomas' Hospital, London, UK. · Int J Clin Pract. · Pubmed #14712900 No free full text.

Abstract: This case report describes a patient who presented with pyrexia of unknown origin allied with hypertriglyceridaemia (16.2 mmol/l) but not hypercholesterolaemia (4.1 mmol/l). Investigations identified the cause of the pyrexia as an adult T-cell lymphoma of natural killer cell phenotype (CD3[+], CD7[+], anti-TCR alpha/beta[+], CD8[+], CD56[+]). Hypertriglyceridaemia has been reported with non-Hodgkin s lymphoma, and an animal model suggests that antilipoprotein lipase antibodies may be made as an immunological response to the tumour. Lymphomas should be considered as part of the differential diagnosis in type IV-V hyperlipidaemia.

Wierzbicki AS, Mikhailidis DP. · Department of Chemical Pathology, St. Thomas' Hospital, Lambeth Palace Road, SE1 7EH, London, UK. · Int J Cardiol. · Pubmed #12104065 No free full text.

Abstract: Epidemiological evidence and clinical trials with fibrate therapy show a clear relationship between low levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular risk. In addition to lowering plasma levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), the hydroxy-methylglutaryl-coenzyme A reductase inhibitors (statins), also raise the levels of HDL-C. This review summarizes the results of five randomized, multicenter studies in hypercholesterolaemic patients in which multiple doses of atorvastatin and simvastatin were compared for their effects on lipids and lipoproteins including HDL-C. Both statins reduced LDL cholesterol and achieved parallel decreases in TG, with atorvastatin showing a slight overall superiority in these studies. Both HDL-C and apolipoprotein (Apo) A-I, its associated apoprotein, were significantly and consistently increased by all doses of simvastatin. However, atorvastatin had a different dose-response effect from simvastatin on both lipid parameters. Whereas HDL-C and Apo A-I were elevated by low doses of atorvastatin, the effect diminished markedly with increasing dose suggesting a possible negative dose-response effect. At higher doses, simvastatin increased HDL-C and Apo A-I significantly more than atorvastatin. These data indicate that statins may not be identical in all their clinical properties relevant to reducing the risks of atherosclerosis.

Mikhailidis DP, Wierzbicki AS. · Department of Molecular Pathology & Clinical Biochemistry, Royal Free and University College Medical School, Royal Free Campus, London NW3 2QG, UK. · Curr Med Res Opin. · Pubmed #11191011 No free full text.

This publication has no abstract.