Background: Social deprivation is associated with higher cardiovascular disease (CVD) morbidity and mortality. We examined whether this is also observed in people with Familial Hypercholesterolaemia (FH). Methods: Subjects with FH and linked secondary care records in Hospital Episode Statistics (HES) were identified from UK Clinical Practice Research Datalink (CPRD) and the Simon Broome (SB) adult FH register. Cox proportional hazards regression estimated hazard ratios (HR) for composite CVD outcomes (first HES outcome of coronary heart disease, myocardial infarction, angina, stroke, transient ischaemic attack, peripheral vascular disease, heart failure, coronary revascularisation interventions (PCI and CABG)) in Index of Multiple Deprivation (IMD) quintiles. Results: We identified 4309 patients with FH in CPRD (1988-2020) and 2956 in the SB register. Both cohorts had considerably fewer subjects in the most deprived compared to the least deprived quintile (60 % lower in CPRD and 52 % lower in SB). In CPRD, the most deprived individuals had higher unadjusted HRs for composite CVD (HR 1.71 [CI 1.22-2.40]), coronary heart disease (HR 1.63 [1.11-2.40]) and mortality (HR 1.58 [1.02-2.47]) compared to the least deprived but these became insignificant after adjusting for age, sex, smoking and alcohol consumption. In the SB register, hazard ratios for composite CVD increased with increasing deprivation quintiles and remained significant after adjustment for age, sex, smoking and alcohol consumption (adjusted HR in quintile 5 vs quintile 1 = 1.83 [1.54-2.17]). Conclusions: Strikingly fewer individuals with FH are identified from lower socioeconomic groups, though the most deprived FH patients have the highest risk of CVD and mortality. In CPRD, this risk was largely explained by smoking and alcohol consumption, but not in the SB register. More effective strategies to detect FH and optimise risk factor management, are needed in lower socioeconomic groups.

Background and Aims: Background: The Simon Broome (SB) FH register has previously reported a 2.2-fold higher Cardiovascular Disease (CVD) mortality in those with "severe-FH" (SFH) compared to "non-severe-FH" (NSFH). Here we examine CVD morbidity over 21 years follow-up, by linking the register participants with the UK secondary care Hospital Episode Statistics (HES) database.

Scintillating calorimeters are cryogenic detectors combining a measurement of scintillation with one of phonons to provide particle identification. In view of developing alkali halide devices of this type able to check the DAMA/LIBRA claim for the observation of dark matter, we have simulated detector performances to determine their sensitivity by two methods with little model-dependence. We conclude that if performance of the phonon channel can be brought in line with those of other materials, an exposure of 10 kg-days would suffice to check the DAMA/LIBRA claim in standard astrophysical scenarios. Additionally, a fairly modest array of 5 kg with background rejection would be able to directly check the DAMA/LIBRA modulation result in 2 years.

Se ha considerado que el engrosamiento intimal patológico (EIP) es un fenotipo de placa benigno. Se presentan los cambios fenotípicos de la placa en un estudio comparativo entre situación basal y seguimiento mediante un estudio de reconstrucción histológica virtual por ecografía intravascular.Se estudió a 61 pacientes con enfermedad coronaria estable del ensayo HEAVEN (89 pacientes aleatorizados al tratamiento estándar con estatinas o atorvastatina 80 mg y ezetimiba 10 mg) por ecografía intravascular seriada de las arterias no culpables. Se compararon los cambios examinando al inicio del estudio y durante el seguimiento 693 segmentos de 5 mm de longitud mediante una nueva puntuación de riesgo, la Liverpool Active Plaque Score (LAPS), los parámetros de la placa y la composición de esta.El EIP es el tipo que mostró mayor aumento de la puntuación de riesgo y, junto con las placas fibrosas, también de la LAPS. El core necrótico (CN) próximo a la luz aumentó tanto en las placas con EIP (22 ± 51,7; p = 0,0001) como en las placas fibrosas (17,9 ± 42,6; p = 0,004), pero disminuyó en el fibroateroma de capa fina (FCF) (–15,14 ± 52,2; p = 0,001). El EIP es el tipo de placa de fibroateroma de capa no fina con mayor probabilidad de transformación a FCF durante el seguimiento (el 11% del total de FCF hallados durante el seguimiento y el 35,9% de los FCF de nueva aparición), pero también el que mostró (junto con las placas fibrosas) menor estabilidad durante el tratamiento hipolipemiante (el 24,7% de los EIP y el 24,5% de las placas fibrosas se mantuvieron estables).En 1 año de seguimiento, el EIP fue el fenotipo de placa más dinámico y se asoció a un aumento de la puntuación de riesgo y de la LAPS (junto con la placa fibrosa), el porcentaje de CN (junto con la placa fibrosa) y el CN próximo a la luz, a pesar de una pequeña reducción del volumen de la placa durante el tratamiento hipolipemiante. El EIP fue el principal origen de los nuevos segmentos con FCF.Pathologic intimal thickening (PIT) has been considered a benign plaque phenotype. We report plaque phenotypic changes in a baseline/follow-up intravascular ultrasound-based virtual histology study.A total of 61 patients with stable coronary artery disease were analyzed from the HEAVEN trial (89 patients randomized between routine statin therapy vs atorvastatin 80 mg and ezetimibe 10 mg) with serial intravascular ultrasound imaging of nonculprit vessels. We compared changes in 693 baseline and follow-up 5-mm long segments in a novel risk score, Liverpool Active Plaque Score (LAPS), plaque parameters, and plaque composition.The PIT showed the highest increase of risk score and, with fibrous plaque, also the LAPS. Necrotic core (NC) abutting to the lumen increased in PIT (22 ± 51.7; P = .0001) and in fibrous plaque (17.9 ± 42.6; P = .004) but decreased in thin cap fibroatheroma (TCFA) (−15.14 ± 52.2; P = .001). The PIT was the most likely of all nonthin cap fibroatheroma plaque types to transform into TCFA at follow-up (11% of all TCFA found during follow-up and 35.9% of newly-developed TCFA), but showed (together with fibrous plaque) the lowest stability during lipid-lowering therapy (24.7% of PIT remained PIT and 24.5% of fibrous plaque remained fibrous plaque).Over the 1-year follow-up, PIT was the most dynamic of the plaque phenotypes and was associated with an increase of risk score and LAPS (together with fibrous plaque), NC percentage (together with fibrous plaque) and NC abutting to the lumen, despite a small reduction of plaque volume during lipid-lowering therapy. The PIT was the main source for TCFA segments.Full English text available from: www.revespcardiol.org/en

Background and aims: Patients with familial hypercholesterolaemia (FH) have an elevated risk of coronary heart disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992, before lipid-lowering therapy with statins was used routinely, and in the periods 1992-2008 and 2008-2016. Methods: 1903 Definite (DFH) and 1650 Possible (PFH) patients (51% women) aged 20-79 years, recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2016 for 67,060 person-years. The CHD standardised mortality ratio (SMR) compared to the population in England and Wales was calculated (with 95% Confidence intervals). Results: There were 585 deaths, including 252 from CHD. Overall, the observed 2.4-fold excess coronary mortality for treated DFH post-1991 was significantly higher than the 1.78 excess for PFH (35% 95% CI 3%-76%). In patients with DFH and established coronary disease, there was a significant excess coronary mortality in all time periods, but in men it was reduced from a 4.83-fold excess (2.32-8.89) pre-1992 to 4.66 (3.46-6.14) in 1992-2008 and 2.51 (1.01-5.17) post-2008, while in women the corresponding values were 7.23 (2.65-15.73), 4.42 (2.70-6.82) and 6.34 (2.06-14.81). Primary prevention in men with DFH resulted in a progressive reduction in coronary mortality over the three time-periods, with no excess mortality evident post-2008 (0.89 (0.29-2.08)), although in women the excess persisted (post-2008 3.65 (1.75-6.72)). Conclusions: The results confirm the benefit of statin treatment in reducing CHD mortality, but suggest that FH patients with pre-existing CHD and women with FH may not be treated adequately. (C) 2018 The Authors. Published by Elsevier B.V.

Objectives: To provide a consensus position on the potential use of new therapies in the management of homozygous familial hypercholesterolaemia (HoFH) based on a review of the current standards of care, unmet medical need and new clinical evidence. The term HoFH is used to include compound heterozygous familial hypercholesterolamia as defined in the National Institute for Clincal Excellence guidelines.

Statins are agents widely used to lower LDL-cholesterol (LDL-C) in primary and secondary prevention of coronary heart disease. The five statins available in the UK (simvastatin, pravastatin, fluvastatin, atorvastatin and rosuvastatin) differ in many of their pharmacologic properties. In addition to lowering LDL-C, statins also increase HDL-cholesterol (HDL-C) moderately. There have been rare reports of significant HDL-C decreases in patients commenced on fibrates and when thiazolidinediones are added to fibrates. This is known as a 'paradoxical HDL-C decrease' as both groups of agents usually increase HDL-C. This phenomenon has never been clearly documented following statin therapy. We now describe a patient with type 2 diabetes who showed this paradoxical fall in HDL-C (baseline HDL-C: 1.8 mmol/L; on simvastatin 40 mg HDL-C 0.6 mmol/L; on atorvastatin 20 mg HDL-C 0.9 mmol/L) with a similar decrease in apolipoprotein A1. No similar decrease was observed with pravastatin and rosuvastatin therapy. This phenomenon appeared to be associated with statin treatment and not a statin/fibrate combination. Our patient clearly demonstrated a paradoxical HDL-C fall with simvastatin and atorvastatin, but not pravastatin or rosuvastatin. Simvastatin and atorvastatin share many pharmacokinetic properties such as lipophilicity while pravastatin and rosuvastatin are relatively hydrophilic and are not metabolized by cytochrome P450 3A4. However, these characteristics do not explain the dramatic reductions in HDL-C observed.

Objective: To examine all-cause and cardiovascular mortality in patients with severe hypertriglyceridaemia.Methods: 337 patients aged less than 80 years (47 with diabetes, 75 women) with a fasting triglyceride concentration on at least two occasions of > 5.0 mmol/l were registered by 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2008 for 4353 person-years. The standardised mortality ratio (SMR) was calculated by comparison with the general population.Results: The mean untreated total cholesterol concentration was 9.8 (SD 3.6) mmol/l for men and 11.9 (7.2) mmol/l for women and the corresponding geometric mean triglyceride concentration was 12.6 (inter-quartile range 7.3, 21.6) and 15.7 (8.2, 29.2) mmol/l. There were 70 deaths, including 35 from CHD and 7 from stroke. The SMR for CHD was raised at 327 (95% confidence intervals 228, 455; p < 0.0001) and remained elevated after excluding patients with diabetes at registration (SMR = 287, 95% CI 190, 419; p < 0.0001), and after excluding patients with CHD at registration (SMR = 259, 95% CI 158, 400; p = 0.0003). The increased SMR was most marked in younger men aged 40-59 years (SMR = 544, 95% CI 304, 897; p < 0.0001). The SMR for stroke for patients aged 20-79 years was raised at 262 (95% CI 105, 540; p = 0.04), as was all-cause mortality at 164 (95% CI 129, 208; p < 0.001).Conclusion: Severe hypertriglyceridaemia is associated with a substantially increased mortality from cardiovascular disease, even in the absence of diabetes. In addition to lowering triglyceride concentrations to reduce the risk of pancreatitis, treatment should aim to reduce the overall cardiovascular risk. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Aims Dyslipidaemia in Type 2 diabetes mellitus (T2DM) is one of the major contributors in the pathogenesis of atherosclerosis. Thiazolidinediones (TZD), a class of drugs used in the treatment of T2DM, also modify lipids, especially lowering serum triglycerides and raising high-density lipoprotein cholesterol (HDL-C).Methods We describe five patients taking rosiglitazone and a fibrate who showed a paradoxical fall in HDL-C, which would have been missed if HDL-C had not been routinely monitored. This could have had a major impact in increasing the cardiovascular risk in these patients.Results Our five patients showed marked variation in both the decrease in serum HDL-C (50-89%) and also in the time taken for recovery of HDL-C after withdrawal of rosiglitazone (between 5 and 20 weeks). Apolipoprotein A1 mirrored the drop in HDL-C in four of the five patients but in one subject this was not seen, suggesting the possibility of multiple mechanisms leading to the phenomenon described, perhaps involving HDL metabolism. Improvements in glycaemic control with rosiglitazone (absolute HbA(1c) reduction between 0.6 and 3.0%) were seen in four of our patients. This suggests that the peroxisomal proliferator-activated receptor gamma signalling pathways relevant to glucose homeostasis were intact.Conclusion As atherosclerosis is associated with a decrease in the HDL-C level, our observations reinforce the message that HDL-C should be measured before and after the commencement of rosiglitazone and also on increasing the dosage

Clinical trials have shown that ezetimibe significantly improves lipid profiles when used as monotherapy or in combination with a statin or fibrate. To assess its effect in clinical practice, a retrospective audit of changes in total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) was conducted in 180 hospital outpatients (mean age 57 years, 58% male) who received ezetimibe for at least 4 weeks. When added to existing therapy, (n = 164) mean reductions in TC and LDLC were 19 and 26%, respectively, larger falls occurring in those already on a statin than when on a fibrate or when used as monotherapy. Bigger mean reductions in TC and LDLC (25 and 36%, respectively) were seen in patients already on a statin and fibrate where ezetimibe replaced the fibrate (n = 16). There were a large range of TC and LDLC responses in each treatment group which are likely to relate, at least in part, to individual variability in cholesterol absorption. As expected from the improvement in TC and LDLC, more patients achieved recognised cholesterol targets after ezetimibe use. The response to ezetimibe in routine practice appears to be consistent with that seen in clinical trials.

Whilst treatment with fibric-acid derivatives is usually associated with an increase in highdensity lipoprotein (HDL) cholesterol, a few hyperlipidaemic patients have shown a paradoxical fall.':" In these patients the profound hypoalphalipoproteinaemia has been induced by ciprofibrate, 1.47 bezafibratef-? or fenofibrate.' This effect may depend on the dose" and its absence of reproducibility in some patients suggests an interaction between the drug and other factors." Simultaneously with the decrease in HDL-cholesterol, a profound reduction in apolipoprotein AI (apoAI) is also seen. Whether the reduction in apoAI results from reduced synthesis or increased breakdown or both has not yet been established. We have therefore studied the metabolism of apoAI and apoAll in a patient in whom ciprofibrate at a daily dose of 200 mg had produced a reproducible reduction in HDL cholesterol.

The serum theophylline concentration was determined in 150 asthmatic patients who received treatment from General Practitioners in the Exeter Health District. The serum theophylline concentration was below the therapeutic range in 75% of the patients evaluated. There was no correlation between serum concentration and daily dose, even when the latter was calculated with respect to bodyweight or body surface area. It was concluded that a theophylline Therapeutic Drug Monitoring (TDM) service should be available for general practice patients.