See Kwok

Familial hypercholesterolaemia commonly presents with achilles tenosynovitis

Background: Patients with heterozygous familial hypercholesterolaemia (HeFH) develop tendon xanthomata (TX), most commonly in their Achilles tendons. Even before tendons are chronically enlarged, tenosynovitis may occur and medical advice be sought. Untreated HeFH carries a high risk of premature coronary heart disease, which can be ameliorated by early diagnosis. Objective: To determine the prevalence of episodes of Achilles tendon pain in HeFH before its diagnosis. Methods: Patients with definite HeFH (Simon Broome criteria) attending a lipid clinic were identified. They completed a questionnaire asking about symptoms relating to their Achilles tendons. Unaffected spouses or cohabiting partners served as controls. Results: 133 patients (47% men) and 87 controls (51% men) participated. TX had been recognised by the referring physicians in <5% of cases. However, 62 (46.6% (95% confidence interval (CI) 38.1 to 55.1)) patients had experienced one or more episodes of pain in one or both Achilles tendons lasting >3 days, whereas only 6 (6.9% (1.6 to 12.2)) controls had done so (difference p<0.001; likelihood ratio 6.75). Typically, in the patients with HeFH the pain lasted 4 days (median). It was described as severe or very severe in 24/62 (38.7% (30.4 to 47.0)) patients with HeFH, but never more than moderate in controls. 35 (26.3% (18.8 to 33.8)) patients with HeFH had consulted a doctor about Achilles tendon pain, but in no case had this led to a diagnosis of HeFH. None of the controls had consulted a doctor. Conclusions: Measurement of serum cholesterol in patients presenting with painful Achilles tendon could lead to early diagnosis of HeFH.

The effect of an apolipoprotein A-I–containing high-density lipoprotein–mimetic particle (CER-001) on carotid artery wall thickness in patients with homozygous familial hypercholesterolemia: The Modifying Orphan Disease Evaluation (MODE) study

BACKGROUND Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease because of exposure to elevated low-density lipoprotein cholesterol (LDL-C) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for cardiovascular disease prevention, but the residual risk in HoFH remains high, emphasizing the need for additional therapies. In the present study, we evaluated the effect of serial infusions with CER-001, a recombinant human apolipoprotein A-I (apoA-I)-containing high-density lipoprotein-mimetic particle, on carotid artery wall dimensions in patients with HoFH. METHODS AND RESULTS Twenty-three patients (mean age 39.4 ± 13.5 years, mean LDL-C 214.2 ± 81.5 mg/dL) with genetically confirmed homozygosity or compound heterozygosity for LDLR, APOB, PCSK9, or LDLRAP1 mutations received 12 biweekly infusions with CER-001 (8 mg/kg). Before and 1 hour after the first infusion, lipid values were measured. Magnetic resonance imaging (3-T magnetic resonance imaging) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. After CER-001 infusion, apoA-I increased from 114.8 ± 20.7 mg/dL to 129.3 ± 23.0 mg/dL. After 24 weeks, mean vessel wall area (primary end point) decreased from 17.23 to 16.75 mm(2) (P = .008). A trend toward reduction of mean vessel wall thickness was observed (0.75 mm at baseline and 0.74 mm at follow-up, P = .0835). CONCLUSIONS In HoFH, 12 biweekly infusions with an apoA-I-containing high-density lipoprotein-mimetic particle resulted in a significant reduction in carotid mean vessel wall area, implying that CER-001 may reverse atherogenic changes in the arterial wall on top of maximal low-density lipoprotein-lowering therapy. This finding supports further clinical evaluation of apoA-I-containing particles in patients with HoFH.

Progestogens of varying androgenicity and cardiovascular risk factors in postmenopausal women receiving oestrogen replacement therapy

objective  Medroxyprogesterone (MP) was used as the progestogen in randomized clinical trials of postmenopausal hormone replacement on cardiovascular risk. To attempt to understand the lack of benefit in these trials, we have examined the effects of MP and two other progestogens, the less androgenic desogestrel (DG) and the more androgenic norethisterone (NE), on cardiovascular risk factors against a background of oestrogen therapy.

Measurement of plasma small-dense LDL concentration by a simplified ultracentrifugation procedure and immunoassay of apolipoprotein B

BACKGROUND Existing methods for detecting small-dense low-density lipoprotein (SD-LDL) are either semiquantitative (e.g., gradient gel electrophoresis) or require specialised laboratory methods (e.g., density-gradient ultracentrifugation, DGU). METHODS We report a method in which plasma was adjusted to a density (D) of 1.044 and 1.060 g/ml, respectively, in two tubes, both of which underwent ultracentrifugation (UC). A measure of SD-LDL apolipoprotein B (apo B) was obtained by subtraction of the apo B concentration in D>1.060 g/ml lipoproteins from that in D>1.044 g/ml lipoproteins to correct for apo B associated with lipoprotein (a) [Lp(a)]. This procedure was evaluated in paired plasma samples in healthy men (n=62) and in age-matched healthy women (n=74) and in age-matched primary dyslipidaemic men (n=72) and women (n=29) and compared with an established density-gradient ultracentrifugation (DGU) method. RESULTS The dyslipidaemic patients had either decreased high-density lipoprotein cholesterol (HDL-C) and/or increased triglycerides. In dyslipidaemic men, SD-LDL apo B level (23 [5-77] mg/dl) was significantly higher than in healthy men (P<0.001). In dyslipidaemic women, the SD-LDL apo B levels (11 [4-71] mg/dl) were significantly higher than in healthy women (7 [1-45] mg/dl; P<0.005). The concentration of SD-LDL apo B correlated inversely with HDL-C in both women (r=-0.280: P<0.005) and men (r=-0.464; P<0.0001) and positively with triglyceride concentration in both women (r=0.213; P<0.05) and men (r=0.592: P<0.0001). Correction for apo B in Lp(a) increased the analytical variation, which was 12% for apo B at D=1.044-1.060 g/ml and 9% for apo B measured at D>1.044 g/ml. Although the correlation between the new method and DGU results was high (r=0.830; P<0.0001, n=43), the concentration of apo B at D>1.044 g/ml correlated strongly with both corrected results (r=0.978; P<0.0001; n=237) and also with SD-LDL isolated using the DGU method (r=0.832; P<0.0001). Results at D>1.044 g/ml showed the expected correlations both with HDL-C (r=-0.465: P<0.0001) and triglycerides (r=0.526; P<0.0001). CONCLUSIONS The new method gave results consistent with earlier published findings using other techniques. Further simplification of the method using a single-density spin at D>1.044 g/ml appears feasible and may provide an easier quantitative method for clinical use.

Extended-release niacin with laropiprant : a review on efficacy, clinical effectiveness and safety.

Introduction: Although treatment with statins reduces cardiovascular (CV) events in patients with dyslipidemia, a residual 60 – 70% CV risk remains. This CV risk may be inversely related to high-density lipoprotein-cholesterol (HDL-C). Interest in niacin has re-emerged because of its HDL-C raising effects. The flushing associated with niacin which has previously affected patient compliance can now be significantly blocked with laropiprant (LRPT). Areas covered: This review aims to assess the efficacy, clinical effectiveness and safety of extended-release niacin (ERN) with LRPT. The authors searched PubMed and MEDLINE for literature published between January 2006 and November 2011, for efficacy, clinical effectiveness and safety reports of ERN with LRPT. Expert opinion: Niacin has been shown to prevent CV events, reduce mortality and has beneficial effects on vascular endothelial function. Evidence suggests that this is due to its broad-spectrum lipid altering properties, including lowering lipoprotein (a) (Lp(a)), and its pleiotropic actions. While side effects associated with niacin have limited its use in the past, the extended-release formulations and co-administration of LRPT have increased its tolerability, particularly by reducing flushing. The authors advise that ERN should be used in patients with a high risk of cardiovascular disease, who have failed to reach conventional targets.

Effect of Extended‐Release Niacin on High‐Density Lipoprotein (HDL) Functionality, Lipoprotein Metabolism, and Mediators of Vascular Inflammation in Statin‐Treated Patients

Background The aim of this study was to explore the influence of extended-release niacin/laropiprant (ERN/LRP) versus placebo on high-density lipoprotein (HDL) antioxidant function, cholesterol efflux, apolipoprotein B100 (apoB)-containing lipoproteins, and mediators of vascular inflammation associated with 15% increase in high-density lipoprotein cholesterol (HDL-C). Study patients had persistent dyslipidemia despite receiving high-dose statin treatment. Methods and Results In a randomized double-blind, placebo-controlled, crossover trial, we compared the effect of ERN/LRP with placebo in 27 statin-treated dyslipidemic patients who had not achieved National Cholesterol Education Program-ATP III targets for low-density lipoprotein cholesterol (LDL-C). We measured fasting lipid profile, apolipoproteins, cholesteryl ester transfer protein (CETP) activity, paraoxonase 1 (PON1) activity, small dense LDL apoB (sdLDL-apoB), oxidized LDL (oxLDL), glycated apoB (glyc-apoB), lipoprotein phospholipase A2 (Lp-PLA2), lysophosphatidyl choline (lyso-PC), macrophage chemoattractant protein (MCP1), serum amyloid A (SAA) and myeloperoxidase (MPO). We also examined the capacity of HDL to protect LDL from in vitro oxidation and the percentage cholesterol efflux mediated by apoB depleted serum. ERN/LRP was associated with an 18% increase in HDL-C levels compared to placebo (1.55 versus 1.31 mmol/L, P<0.0001). There were significant reductions in total cholesterol, triglycerides, LDL cholesterol, total serum apoB, lipoprotein (a), CETP activity, oxLDL, Lp-PLA2, lyso-PC, MCP1, and SAA, but no significant changes in glyc-apoB or sdLDL-apoB concentration. There was a modest increase in cholesterol efflux function of HDL (19.5%, P=0.045), but no change in the antioxidant capacity of HDL in vitro or PON1 activity. Conclusions ERN/LRP reduces LDL-associated mediators of vascular inflammation, but has varied effects on HDL functionality and LDL quality, which may counter its HDL-C-raising effect. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01054508.

Apolipoprotein B100 is a better treatment target than calculated LDL and non-HDL cholesterol in statin-treated patients.

Introduction Clinical trials have shown that apolipoprotein B100 (apoB) is better than calculated low-density lipoprotein cholesterol (c-LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) as a target for statin treatment. However, there are no published reports of how well these targets are reached in patients with more severe hyperlipidaemias than represented in trials, as seen in lipid clinics. Methods We audited 195 patients attending a tertiary centre lipid clinic, who had been treated with a statin for more than one year. We measured total cholesterol, HDL-cholesterol (HDL-C) and triglyceride and from these calculated LDL-cholesterol (LDL-C) and non-HDL-C. We determined the average measured apoB values, at critical target values of LDL-C and non-HDL-C, by linear regression and compared them with values of apoB considered equivalent to these cholesterol indexes by expert groups. We also assessed the number of patients, both before and after treatment, in whom c-LDL-C and non-HDL-C could not be calculated due to hypertriglyceridaemia. Results At the LDL-C target of 2.6 mmol L−1 and the non-HDL-C target of 3.4 mmol L−1, the measured apoB values were significantly higher than consensus apoB target values. The difference was most marked for c-LDL-C in hypertriglyceridaemic subjects and for non-HDL-C in patients without hypertriglyceridaemia. A similar pattern was seen using centile-derived consensus values but the differences were accentuated because this approach generates lower equivalent consensus apoB values. Conclusion ApoB offers a more consistent treatment target independent of hypertriglyceridaemia and would obviate technical problems related to high triglycerides.

Indices of Obesity and Cardiovascular Risk Factors in British Women

Background: Obesity increases cardiovascular risk through effects on blood pressure, lipoproteins, coagulation factors and inflammatory cytokines, but in women variation in fat distribution complicates these relationships. Central (maletype or visceral) obesity confers greater risk than the more generalised (female) type. This is recognised by the metabolic syndrome which employs waist circumference rather than body mass index (BMI). We examined the relationships of several indices of fat distribution with cardiovascular risk factors in a large cohort of UK women. Material and Methods: 13,389 female department store employees aged 30–65 years not receiving exogenous hormones completed a health questionnaire. Their blood pressure, weight, height, waist and hip circumference, serum cholesterol low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides, C-reactive protein (CRP) and plasma fibrinogen were measured. Re-sults: There was a progressive rise in blood pressure, total cholesterol, LDL-C, triglycerides, fibrinogen and CRP with age. After adjustment for these age effects, BMI was most closely related to blood pressure, whereas the waist to height ratio (WHTR) correlated more closely with the other risk factors than BMI, waist circumference or waist to hip ratio (WHPR). Conclusions: Inclusion of height in the definition of metabolic syndrome will produce a clearer association between waist circumference and cardiovascular risk factors. Hypertension may be linked to the metabolic syndrome by its association with general obesity rather than specifically by central obesity.

Knowledge gaps in the management of familial hypercholesterolaemia. A UK based survey

BACKGROUND AND AIMS Untreated individuals with familial hypercholesterolaemia (FH) are at increased risk of developing premature cardiovascular disease (CVD). Early diagnosis and treatment can result in a normal life expectancy. A recent survey commissioned by the European Atherosclerosis Society (EAS) reported a lack of awareness of FH in the general population. We conducted a survey to assess knowledge among healthcare professionals involved in the assessment and management of cardiovascular risk and disease in the United Kingdom. METHODS A survey designed to assess knowledge of diagnostic criteria, risk assessment, the role of cascade screening, and management options for patients with FH was distributed to 1000 healthcare professionals (response rate 44.3%). The same survey was redistributed following attendance at an educational session on FH. RESULTS 151 respondents (40.5%) reported having patients under their care who would meet the diagnostic criteria for FH, but just 61.4% recognized that cardiovascular risk estimation tools cannot be applied in FH, and only 22.3% understood the relative risk of premature CVD compared to the general population. Similarly, just 65.9% were aware of recommendations regarding cascade screening. CONCLUSIONS The prevalence and associated risk of FH continue to be underestimated, and knowledge of diagnostic criteria and treatment options is suboptimal. These results support the recent Consensus Statement of the EAS and production of quality standards by the National Institute for Health and Care Excellence. Further work is required to formulate interventions to improve FH awareness and knowledge, and to determine the effect these interventions have on patient outcomes.

Increased C-reactive protein levels in overweight and obese women taking exogenous hormones: the United Kingdom Women's Heart Study (UKWHS).

Objective  Women’s cardiovascular risk factors, including inflammatory markers such as C‐reactive protein (CRP) which is emerging as a major association with cardiovascular disease (CVD) risk, can be influenced by the oral contraceptive (OC) pill in premenopausal and hormone replacement (HR) in postmenopausal women and by central adiposity which is associated with a heightened inflammatory state. The interaction between central obesity and different hormone use in both pre and postmenopausal women has not previously been reported in a study spanning the whole age range associated with hormone use.