Hyperlipidemias: Betteridge DJ

Betteridge DJ. · Endocrinology and Metabolism, Department of Medicine, University College London Medical School, London, UK. · Diabetes Res Clin Pract. · Pubmed #15885846 No free full text.

Abstract: Patients with type 2 diabetes or the metabolic syndrome have an elevated risk of developing cardiovascular disease (CVD). Until recently, strategies to reduce cardiovascular risk in these patients focused mainly on controlling glycemia and blood pressure as a means of preventing disease progression. However, the metabolic abnormalities that cluster both in patients with type 2 diabetes and the metabolic syndrome are all independent risk factors for atherogenesis. There is now substantial evidence that dyslipidemia is an important, modifiable risk factor for CVD in patients with type 2 diabetes or the metabolic syndrome. Recent sub-group analyses of landmark statin trials, such as the Heart Protection Study (HPS), confirm that the benefits of intensive statin therapy on CVD risk extend to patients with type 2 diabetes, irrespective of baseline lipid levels. In addition, the Collaborative AtoRvastatin Diabetes Study (CARDS), the first statin study to focus solely on patients with type 2 diabetes, was stopped early due to the overwhelming benefits of statin therapy on cardiovascular risk in a study population who previously would not have been considered dyslipidemic (mean baseline low-density lipoprotein cholesterol [LDL-C], 3.0 mmol/l [116 mg/dl]). As a result, treatment guidelines are setting increasingly stringent goals for LDL-C levels in an attempt to reduce cardiovascular risk. However, with physicians estimating that approximately 50% of patients with type 2 diabetes do not achieve these goals, initiation of appropriate, effective and rapid-acting statin therapy is paramount in these high-risk patients.

Carmena R, Betteridge DJ. · Endocrine Service, Hospital Clínico Universitario, University of Valencia, Avda Blasco Ibañez 15, 46010 Valencia, Spain. · Semin Vasc Med. · Pubmed #15861314 No free full text.

Abstract: Lipid abnormalities play an important part in raising the cardiovascular risk in diabetic subjects. The main components of diabetic dyslipidemia are increased plasma triglycerides, low concentration of high-density lipoprotein cholesterol, preponderance of small, dense low-density lipoprotein, and excessive postprandial lipemia. Small, dense low-density lipoprotein, the elevation in remnant triglyceride-rich lipoprotein particles, and the low high-density lipoprotein are the most powerful atherogenic components. The coexistence of these three factors strongly aggravates the lipid accumulation in the arterial wall and the formation of atherosclerotic plaques. The position of diabetes in cardiovascular risk assessment has been recently reviewed in the Harmonized Clinical Guidelines on Prevention of Atherosclerotic Vascular Disease. In general, patients with diabetes carry a high risk for cardiovascular disease, but the absolute risk varies depending on the type of diabetes, age, and population baseline risk. The Adult Treatment Program III (ATP III) and the American Heart Association have designated diabetes as a high-risk condition and recommended intensive risk-factor management. Concerning therapeutic targets, both ATP III and the American Diabetes Association (ADA) guidelines have identified low-density lipoprotein cholesterol as the first priority of lipid lowering, and the optimal level was set at less than 2.6 mmol/L (100 mg/dL). There is strong evidence, coming from landmark secondary prevention studies, that LDL lowering in people with diabetes is associated with significant clinical benefits. The benefits of statin therapy in type 2 diabetics can no longer be questioned. Ongoing clinical trials will help clarify the question of whether increasing high-density lipoprotein cholesterol with fibrates in the presence of low low-density lipoprotein levels (lower than 3.4 mmol/L, or 130 mg/dL) will be more beneficial than statin therapy alone. The new paradigms in risk-reduction therapies for type 2 diabetic subjects are focused on cardiovascular disease prevention, rather than only on glucose or lipid control. Therapeutic lifestyle changes are considered primary therapies for hyperglycemia and coexisting metabolic syndrome, which can be diagnosed in more than half of type 2 diabetes subjects. New perspectives of lipid management in type 2 diabetes should take into account that insulin resistance, increased lipolysis, and overproduction of large, buoyant, very low density lipoprotein particles are at the base of diabetic dyslipidemia. Accordingly, drugs acting in the regulatory steps of very low density lipoprotein assembly should be developed. Activation of peroxisome proliferator activated receptor alpha (PPARalpha), as occurs with fibrates, lowers free fatty acids (FFAs) and triglyceride levels. PPARgamma agonism, as demonstrated by the thiazolidinediones, increases triglyceride lipolysis, FFA transport, and conversion of FFAs to triglycerides. As separate activation of PPARalpha and PPARgamma improves lipid metabolism, the development of new drugs integrating PPARalpha and PPARgamma activity (PPAR-alpha/gamma agonists) is a promising line that may further improve insulin resistance, FFA metabolism, and consequently, atherogenic diabetic dyslipidemia.

Betteridge DJ. · Department of Medicine, Sir Jules Thorn Institute, The Middlesex Hospital, London, UK. · Acta Diabetol. · Pubmed #11829449 No free full text.

Abstract: Compared with non-diabetic individuals, patients with diabetes have a two- to four-fold greater risk of myocardial infarction, and growing evidence suggests that dyslipidaemia contributes significantly to this excess risk. Based on evidence from the major trials of HMG-CoA reductase inhibitors (statins), the American Diabetes Association have published updated guidelines that outline priorities for the treatment of diabetic dyslipidaemia. These guidelines emphasise that low density lipoprotein (LDL) cholesterol is the first priority for lipid lowering. All diabetic patients with, or at risk of, coronary heart disease (CHD) should be treated to an LDL cholesterol goal of < or = 2.6 mmol/L (100 mg/dL). The recent Joint European Task Force on Coronary Prevention recommend similar goals: total cholesterol <5.0 mmol/L (190 mg/dL) and LDL cholesterol <3.0 mmol/L (115 mg/dL). Both the ADA and Joint European Task Force recommend statins as first choice hypolipidaemic therapy for patients with diabetic dyslipidaemia. Ongoing trials will provide further evidence of the benefits of lipid-lowering therapy with statins in reducing CHD risk in patients with type 2 diabetes. Results from these studies will likely add further support to the recommendations to use statins in the overall management of diabetic patients.

Kaplan F, Al-Majali K, Betteridge DJ. · Department of Medicine, Royal Free and University College Medical School, The Middlesex Hospital, London, UK. · J Cardiovasc Risk. · Pubmed #11550999 No free full text.

Abstract: It is clear that the PPAR receptors are exciting targets for therapeutic compounds likely to impact on insulin sensitivity, lipid and glucose homeostasis and vascular disease. The PPARgamma receptor agonists rosiglitazone and pioglitazone are very useful additions to the treatment options for type 2 diabetes. Currently they have limited licences, particularly in Europe, and hopefully as further clinical trial data becomes available these will be extended. Clinical outcome studies are important to ensure that the surrogate effects on glucose and other parameters translate into improved outcomes. There is exciting potential for these agents with the possibility of a combination of effects not only on glucose and lipid homeostasis but also on coagulation and thrombosis, blood pressure and microalbuminuria, which are likely to impact on vascular disease. If the current lack of evidence of serious hepatic toxicity persists they have an advantage over metformin in terms of tolerability and can be used in patients with impaired renal function. In addition to potential effects on diabetic outcome it will be of tremendous interest to determine whether these compounds, which improve insulin sensitivity and beta-cell function, will impact on the natural history of the disease. From what is known of the PPAR receptor systems it is likely that compounds acting as agonists or partial agonists for these receptors will have differing effects and it is possible to envisage the tailoring of compounds to enhance wanted effects and diminish unwanted effects, particularly fluid retention and weight gain. The future certainly looks exciting in this area.

Betteridge DJ. · Royal Free and University College of Medical School, University College London, UK. · Diabetes Obes Metab. · Pubmed #11225757 No free full text.

Abstract: Dyslipidaemia is an important component of the metabolic syndrome observed in patients with type 2 diabetes, and is characterized by moderate hypertriglyceridaemia and low levels of high-density lipoprotein (HDL) cholesterol concentrations. Dyslipidaemia contributes to increased vascular risk and is therefore a good target for therapeutic intervention in the form of glycaemic control, lifestyle measures and hypolipidaemic drugs. It is proposed that lipid abnormalities in type 2 diabetes are secondary consequences of insulin resistance. Any approach that lowers insulin resistance would be anticipated to have a beneficial effect on dyslipidaemia, but in many cases patients with type 2 diabetes fail to achieve normal lipidaemia through diet, exercise and glycaemic control. Subgroup analyses of major clinical trials suggests that lipid-lowering therapy reduces CHD risk in patients with diabetes, but trials performed specifically in populations of patients with diabetes are ongoing. Until then, patients with type 2 diabetes who have established CHD or high individual risk already warrant aggressive lipid-lowering pharmacotherapy. In the author's view, when ongoing studies are complete it is likely that most patients with type 2 diabetes will be prescribed lipid-lowering drugs.

Betteridge DJ. · Department of Medicine, University College, London, UK. · Eur J Clin Invest. · Pubmed #10383605 No free full text.

Abstract: Type 2 diabetic patients have an increased risk of cardiovascular disease and, although many factors contribute to this risk, it is likely that diabetic dyslipidaemia plays an important role. Dyslipidaemia in Type 2 diabetic patients is characterized by low levels of HDL cholesterol and high triglyceride levels. In Type 2 diabetes, the total amount of LDL cholesterol is the same as in healthy people, but there are qualitative changes, e.g. a shift to smaller, denser LDL particles and an increased susceptibility to oxidation. Oxidized LDL may promote the development of atherosclerosis. It is possible to modify the major abnormalities of diabetic dyslipidaemia by combining lifestyle modifications (e.g. increased physical activity, cessation of smoking and weight reduction) with improved glycaemic control and hypolipidaemic drugs to reduce the burden of CVD within this high-risk population.

Betteridge DJ, Gibson JM, Sager PT. · Department of Medicine, University College London, London, United Kingdom. · Am J Cardiol. · Pubmed #17920365 No free full text.

Abstract: Decreasing C-reactive protein (CRP) in addition to decreasing low-density lipoprotein (LDL) cholesterol may further decrease coronary heart disease risk. The effects of rosuvastatin compared with atorvastatin in achieving a combined target of LDL cholesterol <70 mg/dl and CRP <2 mg/L in 509 patients with type 2 diabetes mellitus was evaluated. CRP decreased significantly versus baseline in both treatment groups. Significantly more patients treated with rosuvastatin achieved the combined end point of LDL cholesterol <70 mg/dl and CRP <2 mg/L compared with atorvastatin by the end of the study period (58% vs 37%; p <0.001 vs atorvastatin). In conclusion, CRP was effectively decreased in patients with type 2 diabetes receiving rosuvastatin or atorvastatin, whereas rosuvastatin decreased LDL cholesterol significantly more than atorvastatin.

Soedamah-Muthu SS, Colhoun HM, Thomason MJ, Betteridge DJ, Durrington PN, Hitman GA, Fuller JH, Julier K, Mackness MI, Neil HA, Anonymous00138. · Royal Free and University College London Medical School, London, UK. · Atherosclerosis. · Pubmed #12818407 No free full text.

Abstract: The effect of statin therapy on subclasses of LDL, VLDL and HDL lipoproteins is unclear. We compared changes in serum lipids, apolipoproteins and nuclear magnetic resonance (NMR) spectroscopy measured lipoprotein subclass concentration and average particle size over a minimum 6 months treatment period of atorvastatin 10 mg vs. placebo in 122 men and women. All subjects had type 2 diabetes and a modest dyslipidaemia (mean LDL-cholesterol 3.2 mmol/l and median triglycerides 1.8 mmol/l) and had a previous myocardial infarction. Compared with placebo, atorvastatin therapy was associated with a greater decrease in medium VLDL (median within person change -13.4 vs. -5.9 nmol/l, P<0.001 adjusted for baseline level), small VLDL (median change -17.8 vs. -8.1 nmol/l, P=0.002), large LDL (mean within person change -167.9 vs. -48.6 nmol/l, P<0.001) and medium LDL (median within person change -101.8 vs. -22.3 nmol/l, P=0.017). Atorvastatin therapy was also associated with a greater increase in large HDL than placebo (median change 1.40 vs. 0.80 micromol/l, P=0.02) and there was little change in small HDL so that average HDL particle size increased significantly with atorvastatin (P=0.04). In addition to reducing levels of (enzymatically measured) triglyceride, LDL-cholesterol and apolipoprotein B in diabetic patients, atorvastatin significantly reduces NMR measured medium and small VLDL and large and medium LDL, and increases large HDL.

Nourooz-Zadeh J, Smith CC, Betteridge DJ. · Division of Medicine, Department of Medicine, Royal Free and University College Medical School, The Middlesex Hospital, Mortimer Street, W1N 8AA, London, UK. · Atherosclerosis. · Pubmed #11395041 No free full text.

Abstract: Familial hypercholesterolaemia (FH) may be associated with increased oxidative stress which may contribute to atherogenesis. Plasma lipid hydroperoxides (ROOHs), 8-epi PGF(2alpha) and alpha-tocopherol were measured in normal subjects and in newly referred heterozygous FH patients and used as indices of oxidative stress. ROOH levels were higher (+16%), albeit non-significantly, in FH patients than in controls subjects (4.4+/-0.3 vs. 3.8+/-0.3 micromol/l; n=51 and 40, respectively). 8-epi PGF(2alpha) levels were significantly greater (+56%) in the FH patients than in controls (0.43+/-0.06 vs. 0.27+/-0.05 nmol/l; P<0.05; n=14 and 16, respectively). FH patients with vascular disease had significantly higher (+32%) levels of ROOH compared with patients without vascular disease (4.9+/-0.40 vs. 3.7+/-0.33 micromol/l; P<0.05; n=27 and 24, respectively). Similarly, 8-epi PGF(2alpha) concentrations were higher (+100%) in the FH patients with vascular disease than in those without it (0.6+/-0.08 vs. 0.3+/-0.10 nmol/l; P<0.05; n=6 and 8, respectively). Absolute alpha-tocopherol levels in FH patients were similar to those in controls (21.0+/-0.70 vs. 23.8+/-1.30 micromol/l). When alpha-tocopherol levels were expressed relative to cholesterol, however, the concentrations were found to be significantly lower (-43%) in FH patients than in controls (2.9+/-0.10 vs. 5.1+/-0.40 micromol/mmol, P<0.0005). There were no differences in absolute or cholesterol standardised alpha-tocopherol levels in patients with and without vascular disease. These data suggest that oxidative stress is increased in FH-patients and is particularly pronounced in those patients with vascular disease. It is possible that increased oxidative stress may precede the development of vascular disease.

Betteridge DJ. · University College London Medical School, UK. · Int J Clin Pract. · Pubmed #10563066 No free full text.

Abstract: An international multicentre double-blind randomised trial compared the efficacy and safety of cerivastatin (0.025, 0.05, 0.1 and 0.2 mg once daily) with placebo and simvastatin (20 mg) over a period of 12 weeks, with study extensions to 52 and 100 weeks. The primary efficacy parameter was the percentage change in low density lipoprotein cholesterol (LDL-C). This was reduced from the baseline by 12.5% (0.025 mg) to 30.6% (0.2 mg) compared with falls of 2.0% on placebo and 40.3% on simvastatin. All four cerivastatin doses and simvastatin (20 mg) produced significantly greater falls than placebo (p < 0.0001) and the decrease in LDL-C was dose-dependent for cerivastatin. Simvastatin produced significantly greater falls than any cerivastatin dose or placebo (p < 0.0001). The effect was maintained at 1 year but somewhat attenuated at 100 weeks. Significant falls were also seen in serum total cholesterol and triglycerides. High density lipoprotein cholesterol (HDL-C) levels were significantly increased by cerivastatin (0.1 and 0.2 mg) and simvastatin (20 mg) at 12 weeks and increased further by 100 weeks. Mean fasting apolipoprotein A1 and lipoprotein A1 were increased and apolipoprotein B decreased by cerivastatin and simvastatin therapy. All doses of cerivastatin produced significant falls in the total cholesterol/HDL-C ratio at 12 weeks (0.5-1.6) compared with a fall of 2.1 for simvastatin (20 mg). Cerivastatin was well tolerated. Elevations in creatine phosphokinase, aspartate aminotransferase and alanine aminotransferase were mostly minor and transitory. Vital signs, electrocardiogram determinations, urinalysis and ophthalmic assessment showed similar results for both drugs. Cerivastatin, at doses of 0.1 mg and 0.2 mg daily, is considered to be of therapeutic value in the treatment of patients with primary hypercholesterolaemia, with 0.2 mg cerivastatin achieving reductions of LDL-C and total cholesterol similar to those achieved in the WOSCOP and CARE studies.

Thomas EL, Potter E, Tosi I, Fitzpatrick J, Hamilton G, Amber V, Hughes R, North C, Holvoet P, Seed M, Betteridge DJ, Bell JD, Naoumova RP. · The Robert Steiner MR Unit, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. · Atherosclerosis. · Pubmed #17482623 No free full text.

Abstract: Familial combined hyperlipidaemia (FCHL) is a complex genetic disorder conferring high risk of premature atherosclerosis, characterized by high cholesterol and/or triglyceride, low high density lipoprotein (HDL) cholesterol and insulin resistance. We examined whether pioglitazone, added to conventional lipid-lowering therapy, would favourably affect metabolic parameters and alter body fat content. We undertook a randomized, double blind, placebo-controlled study in 22 male patients with FCHL treated with pioglitazone or matching placebo 30 mg daily for 4 weeks, increasing to 45 mg for 12 weeks. Magnetic resonance imaging and proton magnetic resonance spectroscopy were performed to measure adipose tissue (AT) body content as well as intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL) at baseline and after treatment. Significantly improved in the pioglitazone group were: triglyceride/HDL (atherogenic index of plasma) -32.3% (p=0.002), plasma glucose -4.4% (p=0.03), alanine-aminotransferase (ALT) -7.7% (p=0.005) and adiponectin 130.1% (p=0.001). Pioglitazone treatment resulted in a significant increase in total (5.3%, p=0.02) and subcutaneous (7.1%, p=0.003) adipose tissue as well as in soleus-IMCL levels (47.4%, p=0.02) without alteration in intra-abdominal AT or IHCL. Changes in ALT and AST and IHCL were strongly correlated (r=0.72, p<0.01; r=.0.86, p<0.01, respectively). In patients with FCHL on conventional lipid-lowering therapy, the addition of pioglitazone acts favourably on several metabolic parameters.

Betteridge DJ, Rosenson RS. · Endocrinology and Metabolism, Department of Medicine, University College London Medical School, London, UK. · Diabetes Res Clin Pract. · Pubmed #15953502 No free full text.

This publication has no abstract.

Neil HA, Hawkins MM, Durrington PN, Betteridge DJ, Capps NE, Humphries SE, Anonymous00183. · Division Public Health and Primary Health Care, University of Oxford, Oxford OX3 7LF, UK. · Atherosclerosis. · Pubmed #15777544 No free full text.

Abstract: BACKGROUND: The prognosis from coronary heart disease (CHD) for patients with heterozygous familial hypercholesterolaemia has improved substantially since the introduction of HMG Co-A reductase inhibitors (statins), but the effect of lipid-lowering drug therapy combined with dietary and life style advice on non-coronary mortality and the risk of fatal cancer is unclear. METHODS: The cohort of 2871 patients was recruited from 21 outpatient lipid clinics in the UK from 1980 to 1998 and was followed for 22,992 person-years. The standardised mortality ratio (SMR) was calculated from the ratio of the number of deaths observed to the number expected in the general population of England and Wales. RESULTS: There were 169 deaths, including 102 (60.4%) from CHD, and 32 (18.9%) from cancer. The SMR for CHD was 2.5-fold higher than in the general population (95% CI 2.1, 3.1), but the all-cause SMR was not increased (1.1, 95% CI 0.9, 1.3) and non-coronary mortality was significantly lower in men (0.5, 95% CI 0.3, 0.7) and women (0.6, 95% CI 0.4, 0.9). The SMR for all cancers was significantly reduced (0.6, 95% CI 0.4, 0.8) with an 80% reduction in fatal cancers of the respiratory and intra-thoracic organs and a non-significant reduction in fatal cancers of the genitourinary and digestive organs. CONCLUSIONS: Although the study cannot exclude the possibility that statins have anti-cancer activity, the results strongly suggest that giving advice to consume a healthy diet, increase physical activity and stop smoking is associated with a substantial reduction in mortality from cancer.

Neil HA, Seagroatt V, Betteridge DJ, Cooper MP, Durrington PN, Miller JP, Seed M, Naoumova RP, Thompson GR, Huxley R, Humphries SE. · Division of Public Health & Primary Health Care, Institute of Health Sciences, University of Oxford, Old Road, Headington, Oxford OX3 7LF, UK. · Heart. · Pubmed #15547022 links to  free full text

Abstract: OBJECTIVES: To assess the clinical and biochemical factors associated with inter-individual variation in susceptibility to coronary artery disease (CAD) in treated heterozygous familial hypercholesterolaemia. DESIGN: A cross sectional study was conducted of 410 patients recruited from six lipid clinics in the UK. RESULTS: CAD was documented in 104 of the 211 men and in 55 of the 199 women with mean ages of onset of 43.1 and 46.5 years, respectively. CAD was significantly more common in men (49% v 28%, p < 0.001) and in patients who had smoked cigarettes versus patients who had never smoked (51% v 28%, p < 0.001). After adjusting for age, sex, and current smoking status, there were no significant differences between patients with or without CAD in lipoprotein(a), homocysteine, fibrinogen, plasminogen activator inhibitor-1, white blood cell count, body mass index, glucose, triglyceride or total cholesterol. However, high density lipoprotein (HDL) cholesterol concentrations were significantly lower in those with CAD (6%, 95% confidence interval (CI) 1% to 11%, p = 0.03) and this difference was greater in women than men (12% v 2%, p = 0.041). CONCLUSIONS: These results indicate that emerging coronary risk factors appear not to be associated with CAD in adults with treated familial hypercholesterolaemia, but the strong association with smoking suggests that patients should be identified early in childhood and discouraged from ever starting to smoke.

Smith CC, Betteridge DJ. · Department of Medicine, Royal Free and University College Medical School, Sir Jules Thorn Institute, The Middlesex Hospital, Mortimer Street, London WIN 8AA, UK. · Neurosci Lett. · Pubmed #15308295 No free full text.

Abstract: The circulation constitutes a potential source of the beta-amyloid (A beta) protein deposited cerebrally in Alzheimer's disease (AD). Cardiovascular risk factors, including hyperlipidaemia, may be involved in the pathogenesis of AD. Plasma A beta 40 was measured by radioimmunoassay in normal and hyperlipidaemic subjects with the aim of determining if plasma lipid content and/or age correlated with circulating A beta 40 concentration. Plasma A beta 40 levels in hyperlipidaemics were elevated by 20.3% compared to normal subjects. A beta 40 did not correlate with plasma lipids in normal subjects. Age, however, correlated positively with A beta 40 in these individuals and with total cholesterol, low-density lipoprotein (LDL) and triglycerides. No correlations were observed in hyperlipidaemic patients or when the data for the two groups were combined. These data are consistent with ageing, the primary risk factor for AD, but not hyperlipidaemia influencing circulating A beta 40 levels.

Eichenbaum-Voline S, Olivier M, Jones EL, Naoumova RP, Jones B, Gau B, Patel HN, Seed M, Betteridge DJ, Galton DJ, Rubin EM, Scott J, Shoulders CC, Pennacchio LA. · Genomic & Molecular Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, UK. · Arterioscler Thromb Vasc Biol. · Pubmed #14551155 links to  free full text

Abstract: OBJECTIVE: Combined hyperlipidemia is a common disorder, characterized by a highly atherogenic lipoprotein profile and a substantially increased risk of coronary heart disease. The purpose of this study was to establish whether variations of apolipoprotein A5 (APOA5), a newly discovered gene of lipid metabolism located 30 kbp downstream of the APOA1/C3/A4 gene cluster, contributes to the transmission of familial combined hyperlipidemia (FCHL). METHODS AND RESULTS: We performed linkage and association tests on 128 families. Two independent alleles, APOA5c.56G and APOC3c.386G, of the APOA1/C3/A4/A5 gene cluster were overtransmitted in FCHL (P=0.004 and 0.007, respectively). This was paired with reduced transmission of the common APOA1/C3/A4/A5 haplotype (frequency 0.4461) to affected subjects (P=0.012). The APOA5c.56G genotype accounted for 7.3% to 13.8% of the variance in plasma triglyceride levels in probands (P<0.004). The APOC3c.386G genotypes accounted for 4.4% to 5.1% of the variance in triglyceride levels in FCHL spouses (P<0.007), suggesting that this allele marks a FCHL quantitative trait as well as representing a susceptibility locus for the condition. CONCLUSIONS: A combined linkage and association analysis establishes that variation at the APOA1/C3/A4/A5 gene cluster contributes to FCHL transmission in a substantial proportion of northern European families.

Naoumova RP, Bonney SA, Eichenbaum-Voline S, Patel HN, Jones B, Jones EL, Amey J, Colilla S, Neuwirth CK, Allotey R, Seed M, Betteridge DJ, Galton DJ, Cox NJ, Bell GI, Scott J, Shoulders CC. · Genomic and Molecular Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, UK. · Arterioscler Thromb Vasc Biol. · Pubmed #14500288 links to  free full text

Abstract: Background- Combined hyperlipidemia is a common disorder characterized by a highly atherogenic lipoprotein profile and increased risk of coronary heart disease. The etiology of the lipid abnormalities (increased serum cholesterol and triglyceride or either lipid alone) is unknown. METHODS AND RESULTS: We assembled 2 large cohorts of families with familial combined hyperlipidemia (FCHL) and performed disease and quantitative trait linkage analyses to evaluate the inheritance of the lipid abnormalities. Chromosomal regions 6q16.1-q16.3, 8p23.3-p22, and 11p14.1-q12.1 produced evidence for linkage to FCHL. Chromosomes 6 and 8 are newly identified candidate loci that may respectively contribute to the triglyceride (logarithm of odds [LOD], 1.43; P=0.005) and cholesterol (LOD, 2.2; P=0.0007) components of this condition. The data for chromosome 11 readily fulfil the guidelines required for a confirmed linkage. The causative alleles may contribute to the inheritance of the cholesterol (LOD, 2.04 at 35.2 cM; P=0.0011) component of FCHL as well as the triglyceride trait (LOD, 2.7 at 48.7 cM; P=0.0002). CONCLUSIONS: Genetic analyses identify 2 potentially new loci for FCHL and provide important positional information for cloning the genes within the chromosome 11p14.1-q12.1 interval that contributes to the lipid abnormalities of this highly atherogenic disorder.

Neil HA, Huxley RR, Hawkins MM, Durrington PN, Betteridge DJ, Humphries SE, Anonymous00021. · Division Public Health and Primary Health Care, Institute for Health Sciences, University of Oxford, Headington, Oxford, UK. · Atherosclerosis. · Pubmed #12957684 No free full text.

Abstract: BACKGROUND: A clinical diagnosis of familial hypercholesterolaemia (FH) is often made in the absence of tendon xanthomata (TX), which are not usually present before the fourth decade of life. The prognosis of treated non-xanthomatous (TX-) FH is uncertain and the objective of this study was to compare mortality from coronary heart disease (CHD) in patients with treated TX+ (definite) and TX- (possible) heterozygous FH. METHODS: A diagnosis of definite or possible FH was based on raised cholesterol levels (>7.5 mmol/l) and a family history of premature CHD or hypercholesterolaemia. Patients were recruited from 21 outpatient lipid clinics in the UK from 1980 to 1998. The cohort of 1569 patients with TX+ FH were followed for 12754 person years and the cohort of 1302 patients with TX- FH for 10238 person years. The standardised mortality ratio (SMR) was calculated from the ratio of the number of deaths observed to the number expected in the general population of England and Wales (SMR=100 for reference population). FINDINGS AND DISCUSSION: CHD accounted for 64 (63%) of the 102 deaths in the TX+ cohort and 38 (57%) of the 67 deaths in the TX- cohort with the SMR for a fatal coronary event being, respectively, 294 (95% confidence interval 228, 380, P<0.00001) and 205 (95% CI 145, 282, P=0.0001). The similarly elevated CHD mortality risk suggests that, in adulthood, both groups of patients should be treated equally aggressively with HMG Co A reductase inhibitors (statins).

Betteridge DJ, Tuomilehto J. · Department of Medicine, London Medical School, University College, Mortimer Street, London W1T 3AA, UK. · Diabetes Res Clin Pract. · Pubmed #12880688 No free full text.

This publication has no abstract.

Naoumova RP, Betteridge DJ. · MRC Clinical Sciences Centre, Hammersmith Hospital, London, UK · Lancet. · Pubmed #12103282 No free full text.

This publication has no abstract.

Smith CC, Hyatt PJ, Stanyer L, Betteridge DJ. · Department of Medicine, Royal Free and University College Medical School, Sir Jules Thorn Institute, Gower Street Campus, The Middlesex Hospital, Mortimer Street, W1N 8AA, London, UK. · Brain Res. · Pubmed #11277986 No free full text.

Abstract: Tissue accumulation of the cytotoxic beta-amyloid peptide (Abeta) occurs in Alzheimer's disease (AD), one possible source being the platelet. AD and cardiovascular disease may share some risk factors, including hypercholesterolaemia which is associated with increased platelet activity. We examined platelet Abeta release under resting and collagen-stimulated conditions in normocholesterolaemic and hypercholesterolaemic individuals. Resting platelet Abeta efflux was greater in hypercholesterolaemics than in normocholesterolaemics. Collagen-stimulated Abeta release was concentration-dependent and increased in hypercholesterolaemics. Resting Abeta release correlated positively with plasma total cholesterol and low-density lipoprotein (LDL) cholesterol, and inversely with platelet count. These data indicate that abnormal platelet Abeta release occurs in hypercholesterolaemia.

Smith CT, Betteridge DJ. · Department of Medicine, Royal Free and University College Medical School, Sir Jules Thorn Institute, The Middlesex Hospital, London, UK. · Platelets. · Pubmed #11132106 No free full text.

Abstract: Collagen-induced (5-80 microg/ml) efflux of free noradrenaline (NA) and adrenaline (Ad) from platelets in platelet-rich plasma was compared in normal human subjects and heterozygous familial hypercholesterolaemic (FH) patients. Stimulated release of NA and Ad to the plasma (platelet-poor; PPP) increased in a dose-dependent fashion in both normal and FH groups. Under resting conditions (0 microg/ml collagen) PPP NA concentrations were increased in hypercholesterolaemics by 38% (non-significant). The absolute amounts of NA released on stimulation with 5 microg/ml and 10 microg/ml collagen (i.e. the differences between resting and stimulated release) were reduced in hypercholesterolaemics by 45% (p<0.01) and 38% (p<0.02), respectively. Collagen EC50 values for NA and Ad release were increased in hypercholesterolaemics by 118% (p<0.001) and 141% (p<0.05). Combining the data for the normal and FH groups revealed that the collagen EC50 values for NA release correlated positively with plasma total cholesterol (p<0.02) and low-density lipoprotein (p<0.02). These data provide additional evidence for catecholaminergic abnormalities in hypercholesterolaemia.

Betteridge DJ, Colhoun H, Armitage J. · Department of Medicine, University College, London, UK. · Curr Opin Lipidol. · Pubmed #11086336 No free full text.

Abstract: The prevention and treatment of coronary heart disease is a major challenge in the overall management of the patient with type 2 diabetes. Diabetic dyslipidaemia is an important risk factor and is open to therapeutic intervention. However, as yet there are no primary or secondary coronary heart disease prevention trials of lipid-lowering therapy reported in diabetic populations. In this review, on-going clinical trials of lipid-lowering therapy in specific diabetic populations will be described.

Humphries SE, Whittall RA, Hubbart CS, Maplebeck S, Cooper JA, Soutar AK, Naoumova R, Thompson GR, Seed M, Durrington PN, Miller JP, Betteridge DJ, Neil HA, Anonymous00065. · No affiliation provided · J Med Genet. · Pubmed #17142622 No free full text.

Abstract: AIMS: To determine the relative frequency of mutations in three different genes (low-density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK. Patients and METHODS: 409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single-strand conformational polymorphism (SSCP) (exons 3, 4, 6-10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP. RESULTS: Mutations were detected in 253 (61.9%) PATIENTS: 236 (57.7%) carried LDLR, 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9. After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels (LDLR, PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post-statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL-C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL-C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03). CONCLUSIONS: The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK.