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Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder, resulting in elevated triglycerides (TGs), abdominal pain and pancreatitis. Treatment options are limited. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved for the treatment of homozygous familial hypercholesterolaemia. Whether its therapeutic use may be extended to FCS remains unknown. The aim of this study was to evaluate the efficacy and safety of lomitapide in adult patients with FCS.The open-label, single-arm 'LOCHNES' study of lomitapide in FCS enrolled patients18 years with genetically confirmed FCS, elevated fasting TG ≥ 750 mg/dL and history of pancreatitis. Patients were administered lomitapide to the maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26.Eighteen patients were enrolled with median baseline TG levels 1803.5 mg/dL (97.5% CI, 1452-2391 mg/dL). At Week 26, median fasting TGs were reduced to 305 mg/dL (97.5% CI 219-801 mg/dL; 70.5% reduction); median lomitapide dose was 35 mg/day; 13 patients achieved TGs ≤750 mg/dL. Adverse events were mild to moderate and mainly related to gastrointestinal tolerability. Liver imaging at baseline and Week 26 revealed hepatic fat increases from median 12.0%-32.5%, while median hepatic stiffness remained normal. No patient experienced acute pancreatitis or severe abdominal pain during lomitapide treatment.Lomitapide is effective and well tolerated in reducing TGs in FCS patients with a history of pancreatitis. Larger studies are warranted to determine lomitapide effectiveness in FCS.

International audience; The healthcare system of Ukraine was already suffering from several shortfalls before February 2022, but the war of aggression started by the Russian leadership is poised to inflict a further severe blow that will have long-lasting consequences for the health of all Ukrainians. In pre-war Ukraine, noncommunicable diseases (NCDs) contributed to 91% of deaths, especially cardiovascular diseases (67%). Ukrainians have a high prevalence of risk factors for NCDs ranking among the highest levels reported by the World Health Organization (WHO) in the European (EU) Region. Cardiovascular disease is one of the key health risks for the conflict-affected Ukrainian population due to significant limitations in access to health care and interruptions in the supply of medicines and resources. The excess mortality observed during the COVID-19 pandemic, due to a combination of viral illness and chronic disease states, is bound to increase exponentially from poorly treated NCDs. In this report, we discuss the impact of the war on the public health of Ukraine and potential interventions to provide remote health assistance to the Ukrainian population.

Little is known about the role of Lp(a) in the assessment of cardiovascular risk in the paediatric population. Trying to clarify the clinical relevance of Lp(a) in risk stratification, the aim of the study is to evaluate the association between Lp(a) plasma levels in children with familial hypercholesterolaemia (FH) and positive family history for premature cardiovascular disease (pCVD) in first- and second-degree relatives.653 Caucasian children and adolescents (334 females and 319 males), aged 2-17 years, with diagnosis of FH from a paediatric cohort included in the LIPIGEN Network, were selected. We compared family history of pCVD, lipid and genetic profile in two groups based on Lp(a) levels below or above 30 mg/dL. To determine the independent predictors of pCVD, a multivariate logistic regression was used, with all clinical characteristics and blood measurements as predictors.Subjects with Lp(a) 30 mg/dl more frequently reported positive family history of pCVD compared to subjects with Lp(a)≤30 mg/dl (69.90% vs 36.66%, p 0.0001), while did not show differences in terms of median [interquartile range] LDL-cholesterol level (153.00 [88.00 vs 164.50 [90.25] mg/dL, p = 0.3105). In the regression analysis, Lp(a) 30 mg/dl was an independent predictor of family history of pCVD. Comparing subjects with or without family history of pCVD, we reported significant differences for Lp(a) 30 mg/dl (46.25% vs 17.65%, p 0.0001), FH genetic mutation (50.48% vs 40.75%, p = 0,0157), as well as for LDL-cholesterol (p = 0.0013) and total cholesterol (p = 0.0101).Children/adolescents with FH and Lp(a) 30 mg/dl where more likely to have a positive family history of pCVD. Lp(a) screening in children and adolescents with FH may enhance risk assessment and help identify those subjects, children and relatives, at increased pCVD risk.

ODYSSEY APPRISE trial evaluated efficacy and safety of alirocumab in 994 patients with hypercholesterolemia and high CV risk in a real-life setting. The aim of the present report is to detail on the Italian cohort enrolled and treated in the trial.The methodology of the of the multinational, single-arm, Phase 3b open-label ODYSSEY APPRISE (Clinicaltrials.gov: NCT02476006) has been previously reported. 255 Italian patients were enrolled and treated according to the trial protocol. Overall mean exposure to alirocumab was 83.3 ± 27.7 weeks. At week 12, LDL-C decreased by 51.3 ± 23.1% and this reduction was overall maintained for the duration of the study. A similar reduction was observed in patients with and without heterozygous familial hypercholesterolemia (HeFH 50.7% ± 23.9 vs. non-FH, 53.6% ± 19.6). LDL-C was reduced below 1.8 mmol/L and/or by ≥ 50% reduction from baseline in 62% of patients overall (61% in HeFH and 67% in non-FH). Alirocumab was similarly well tolerated in the Italian cohort as in the entire study population and the more common treatment emergent adverse events (TEAEs) were influenza, myalgia and nasopharyngitis. The incidence LDL-C levels25 mg/dl and15 mg/dl, was 8.2% and 2.9% respectively.The efficacy and safety of alirocumab in a real-life setting, in the Italian subgroup of patients are consistent with findings in the entire study population and confirm that alirocumab is a beneficial approach to further reduce LDL-C levels in patients at high CV risk on maximally tolerated conventional lipid lowering treatment.NCT02476006.

Aims As the potential impact of statins on cognitive decline and dementia is still debated, we conducted a meta-analysis of observational studies to examine the effect of statin use on the risk of Alzheimer’s disease (AD) and dementia. Methods and results PubMed, Cochrane, and EMBASE were searched since inception to January 2021. Inclusion criteria were: (i) cohort or case–control studies; (ii) statin users compared to non-users; and (iii) AD and/or dementia risk as outcome. Estimates from original studies were pooled using restricted maximum-likelihood random-effect model. Measure of effects were reported as odds ratio (OR) and 95% confidence intervals (CIs). In the pooled analyses, statins were associated with a decreased risk of dementia [36 studies, OR 0.80 (CI 0.75–0.86)] and of AD [21 studies, OR 0.68 (CI 0.56–0.81)]. In the stratified analysis by sex, no difference was observed in the risk reduction of dementia between men [OR 0.86 (CI 0.81–0.92)] and women [OR 0.86 (CI 0.81–0.92)]. Similar risks were observed for lipophilic and hydrophilic statins for both dementia and AD, while high-potency statins showed a 20% reduction of dementia risk compared with a 16% risk reduction associated with low-potency statins, suggesting a greater efficacy of the former, although a borderline statistical significance (P = 0.05) for the heterogeneity between estimates. Conclusion These results confirm the absence of a neurocognitive risk associated with statin treatment and suggest a potential favourable role of statins. Randomized clinical trials with an ad hoc design are needed to explore this potential neuroprotective effect.

International audience; Background and aimsThis European Atherosclerosis Society (EAS) Task Force provides practical guidance for combination therapy for elevated low-density lipoprotein cholesterol (LDL-C) and/or triglycerides (TG) in high-risk and very-high-risk patients.MethodsEvidence-based review.ResultsStatin-ezetimibe combination treatment is the first choice for managing elevated LDL-C and should be given upfront in very-high-risk patients with high LDL-C unlikely to reach goal with a statin, and in primary prevention familial hypercholesterolaemia patients. A proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor may be added if LDL-C levels remain high. In high and very-high-risk patients with mild to moderately elevated TG levels (>2.3 and < 5.6 mmol/L [>200 and < 500 mg/dL) on a statin, treatment with either a fibrate or high-dose omega-3 fatty acids (icosapent ethyl) may be considered, weighing the benefit versus risks. Combination with fenofibrate may be considered for both macro- and microvascular benefits in patients with type 2 diabetes mellitus.ConclusionsThis guidance aims to improve real-world use of guideline-recommended combination lipid modifying treatment.

The widespread use of statins has largely improved the treatment of hypercholesterolemia, but many patients still fail to achieve the LDL-C targets recommended by guidelines. Furthermore, some patients continue to present a very high cardiovascular (CV) risk or even an extreme risk despite being well treated, mainly due to the presence of co-morbidities such as diabetes or peripheral artery disease, which significantly increase their global CV risk. For these very high CV risk patients, the most recent European guidelines have reviewed the LDL-C goals and recommend an LDL-C reduction of at least 50% and a goal of55 mg/dL or even40 mg/dL. Recent clinical trials have shown that patient stratification based on the presence or absence of atherothrombotic risk factors may represent a valuable tool to identify patients at extremely high CV risk who may benefit more from an aggressive LDL-C-lowering approach. In these patients it may be appropriate to aim for the lowest LDL-C level, independently of recommended goals, with all the available pharmacological approaches.

Lomitapide, a drug for the treatment of homozygous familial hypercholesterolemia patients, reduced total and LDL cholesterol but no significant changes were observed on PCSK9 and Lp(a) plasma levels. Some changes of inflammatory mediators were also observed, including hsCRP, which may suggest an anti-inflammatory effect.

Hypertriglyceridaemia is a highly prevalent disorder worldwide. Genetic and Mendelian randomization studies have suggested that triglyceride (TG)-rich lipoproteins are causal risk factors for coronary heart disease and contribute to the residual cardiovascular risk observed in patients optimally treated with statins. However, clinical trials failed to show cardiovascular benefits of TG-lowering; in this context, trials with omega-3 fatty acids provided contrasting results. Few trials have tested the supplementation of EPA alone rather than the combination of EPA + DHA. The JELIS study showed that EPA 1.8 g/day significantly reduced CV events in hypercholesterolaemic patients given statins, an effect that was independent on lipid reduction. The REDUCE-IT trial showed that high-dose (4 g/day) EPA significantly reduces the incidence of major cardiovascular events compared with placebo in patients with elevated TG levels. The clinical benefit was higher than expected by the reduction of TG-rich lipoprotein levels. Recent data support the efficacy of high-dose EPA supplementation on a background of optimal LDL-C-lowering therapy as a key approach to achieve a further and significant reduction of CV events in very-high CV risk patients with persistent hypertriglyceridaemia. The effect on lipids does not appear to fully explain the CV benefit, and additional mechanisms of action of EPA likely contribute to the cardiovascular protection, including the reduction of inflammation and platelet aggregation. Current guidelines recommend using high-dose EPA in combination with a statin in high/very-high CV risk patients with mild-to-moderate elevation of plasma TG to reduce the residual CV risk.

Among the cardiovascular risk factors, cholesterol-rich atherogenic lipoproteins play a central role in the pathogenesis of atherosclerosis. In middle-aged adults, the size of the total atherosclerotic plaque burden is influenced by both the concentration of circulating atherogenic lipoproteins and the total duration of exposure to these lipoproteins. This review describes the evidence supporting a causal link between lifelong elevations in atherogenic lipoproteins and future risk of atherosclerosis; evidence strengthened by recent epidemiological, genetic, and clinical data. By consequence, adolescence and early adulthood are a crucial time for determining later cardiovascular disease risk. Arguments showing that early optimal lipid control leads to improved outcomes will be presented and suggestions put forward for how those most at risk should be identified and managed.

Background Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data for clinical management and cardiovascular outcomes in ARH. Objectives Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH. Methods Published ARH cases were identified by electronic search. All corresponding authors and physicians known to treat these patients were asked to provide follow-up information, using a standardized protocol. Results We collected data for 52 patients (28 females, 24 males; 31.1 ± 17.1 years of age; baseline LDL-C: 571.9 ± 171.7 mg/dl). During a mean follow-up of 14.1 ± 7.3 years, there was a significant increase in the use of high-intensity statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was 164.0 ± 85.1 mg/dl (−69.6% from baseline), with a better response in patients taking lomitapide (−88.3%). Overall, 23.1% of ARH patients reached LDL-C of Conclusions Despite intensive treatment, LDL-C in ARH patients remains far from targets, and this translates into a poor long-term cardiovascular prognosis. Our data highlight the importance of an early diagnosis and treatment and confirm the fact that an effective treatment protocol for ARH is still lacking.

Objective:A relevant role is emerging for functional foods in cardiovascular prevention. Aim of this study was to assess the effect of a nutraceutical approach on lipid profile and inflammatory cytokines along with vascular remodeling in subjects in primary prevention for cardiovascular disease in a

Obesity is a pro-atherogenic condition and postprandial lipoprotein profile and circulating cytokines changes may contribute to promote the process. The aim of this study is to investigate postprandial metabolic response, lipoprotein oxidation and circulating cytokine levels, after the ingestion of two different meals with different fat/carbohydrate ratio.Ten prepubertal obese boys consumed two meals with the same energy and protein content but with a different carbohydrate to fat ratio: 1) moderate fat (MF): 61% carbohydrate, 27% fat; 2) high fat (HF): 37% carbohydrate, 52% fat. The AUC of glucose and insulin were significantly (p0.05) lower after the HF meal. HF meal was followed by a significant decrease in the cholesterol carried in the HDL fractions, while cholesterol in the small, dense LDL and in the VLDL particles increased, as compared to baseline (p0.05 for all). No differences were found in the cholesterol distribution after the MF meal. Moreover, HDL-C concentration was lower (p0.05) at 300 min after HF vs. MF meal. Oxidized LDL (ox-LDL) concentration increased after the HF meal but not after the MF meal [9.3(2.2) vs 1.8(2.2)% from baseline, P0.02)]. A positive association (r0.3, P0.05) was observed between the densest LDL particles and the ox-LDL plasma levels. A reduction of IL-6 was found at 120 min after the MF [-23.3(5.5) vs -8.4(3.8)% from baseline, P0.05)] compared with the HF meal.A simple change of ≈25% of energy load from fat to carbohydrate in a meal significantly improves postprandial pro-atherogenic factors in obese boys.

Aim of the present Consensus Statement is to provide a comprehensive and up to-date document on the pathophysiology, atherogenicity and clinical significance of low density lipoproteins (LDL) subclasses. We sub-divided our Statement in 2 sections: section I discusses the pathophysiology, atherogenicity and measurement issues, while section II is focused on the effects of drugs and lifestlyle modifications. Suggestions for future research in the field are highlighted at the end of section II. Each section includes Conclusions.

Navzdory soucasným standardům lecby zaměřene na dosaženi cilových hodnot LDL cholesterolu, krevniho tlaku a glykemie maji pacienti s dyslipidemii vysoke rezidualni riziko vzniku vaskularnich přihod. Aterogenni dyslipidemie, zejmena vyssi hodnota triglyceridů a nizka koncentrace HDL cholesterolu, se casto vyskytuje spolu s vyssi koncentraci apolipoproteinu B a non‑HDL cholesterolu u pacientů s diagnostikovanými kardiovaskularnimi onemocněnimi, diabetes mellitus 2. typu, obezitou nebo metabolickým syndromem a je spojena s rezidualnim makrovaskularnim a mikrovaskularnim rizikem. Residual Risk Reduction Initiative (R3i) byla založena proto, aby se touto důležitou problematikou zabývala. Cilem tohoto souhrnneho přehledu je vyzdvihnout skutecnost, že se aterogenni dyslipidemie podili na rezidualnim makrovaskularnim riziku a mikrovaskularnich komplikacich, a doporucit lecebnou intervenci vedouci ke sniženi tohoto rizika, podpořenou důkazy a odborným konsensem. Důležitým prvnim krokem je uprava životniho stylu. Casto je mimo to nutna take farmakoterapie. Přidani niacinu, fibratu nebo ω‑3 mastných kyselin k terapii statiny zlepsuje vsechny lipidove rizikove faktory. Klinicke studie hodnoti, zda maji tyto strategie lepsi klinický přinos než lecba statiny. Zavěrem lze řici, že iniciativa R3i zdůrazňuje potřebu ovlivnit vysokou miru rezidualniho vaskularniho rizika u pacientů s dyslipidemii, kteři jsou leceni prostřednictvim upravy životniho stylu anebo farmakoterapii v souladu se soucasnými standardy lecby.

A meeting of European experts in cardiovascular (CV) disease and lipids was convened in Paris, France, on 10 November 2014 to discuss lipid profile, and in particular atherogenic dyslipidaemia (AD), and associated CV risk. Key points that were raised and discussed during the meeting are summarised in this paper, which also accounts for further discussion and agreement on these points by the group of experts. Elevated levels of low-density lipoprotein cholesterol (LDL-c) are commonly associated with a greater CV risk than low LDL-c levels, and are routinely managed with statins. However, even for patients controlled on statins and achieving low LDL-c levels, abnormal lipid profiles observed in some patients (i.e. elevated triglyceride levels, with/without low levels of high-density lipoprotein cholesterol [HDL-c]) have been linked to the presence of a residual CV risk. Therefore, it is recommended that both triglyceride and HDL-c levels be measured, to allow for the overall CV residual risk to be adequately managed. Favourable safety and clinical data support the combination of statins with other lipid-lowering agents, such as fenofibrate. Patients who have elevated triglyceride levels plus low levels of HDL-c are most likely to achieve clinical benefit from fenofibrate-statin combination therapy. In these patients with AD, achieving target non-HDL-c levels should be a key focus of CV risk management, and the use of non-HDL-c was advocated to provide a better measure of CV risk than LDL-c levels.

Atherosclerosis is a long-term chronic inflammatory disease associated with increased concentrations of inflammatory hepatic markers, such as CRP and fibrinogen, and of peripheral origin, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Peroxisome proliferator-activated receptor (PPAR-)-alpha is a ligand-activated transcription factor that regulates expression of key genes involved in lipid homeostasis and modulates the inflammatory response both in the vascular wall and the liver. PPAR-alpha is activated by natural ligands, such as fatty acids, as well as the lipid-lowering fibrates. PPAR-alpha agonists impact on different steps of atherogenesis: (1) early markers of atherosclerosis, such as vascular wall reactivity, are improved, (2) however, reduced expression of adhesion molecules on the surface of endothelial cells, accompanied by decreased levels of inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6, leads to a decreased leukocyte recruitment into the arterial wall; (3) in later stages of the atherosclerotic process, PPAR-alpha agonists may promote plaque stabilization and reduce cardiovascular events, via effects on metalloproteinases, such as MMP9. Moreover, PPAR-alpha activation by fibrates also impairs proinflammatory cytokine-signaling pathways in the liver resulting in the modulation of the acute phase response reaction via mechanisms independent of changes in lipoprotein levels. Effective coronary artery disease (CAD) prevention requires the use of agents that act beyond low-density lipoprotein cholesterol-lowering. PPAR-alpha agonists appear to comprehensively address some of the abnormalities of the most common clinical phenotypes of the high CAD risk patient of the 21st century such as in the metabolic syndrome and type 2 diabetes: low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein, and a proinflammatory, procoagulant state.

Background: Inflammatory mechanisms are thought to play a key role in the development of atherosclerosis and unstable plaque. In the past, numerous studies have reported that the statins have an antiinflammatory and anti-atherosclerotic effect unrelated to lipid-lowering. However, it is still difficult to estimate the contribution of the specific cholesterol-independent effects of statins in counteracting the atherosclerotic process and its sequelae.

Two large studies in populations selected for cardiovascular disease (CVD) demonstrated that raising high-density lipoprotein (HDL) cholesterol with niacin added to statin therapy did not decrease CVD. We examine the association of lipoprotein subfractions with niacin and changes in coronary stenosis and CVD event risk. One hundred and seven patients from 2 previous studies using niacin in combination with either statin or bile acid-binding resin were selected to evaluate changes in lipoproteins separated by density-gradient ultracentrifugation to progression of coronary artery disease as assessed by quantitative coronary angiography. Improvement in coronary stenosis was significantly associated with the decrease of cholesterol in the dense low-density lipoprotein (LDL) particles and across most of the intermediate density lipoprotein (IDL) and very low density lipoprotein particle density range, but, not with any of the HDL fraction or of the more buoyant LDL fractions. Event-free survival was significantly associated with the decrease of cholesterol in the dense LDL and IDL; there was no association with changes in cholesterol in the HDL and buoyant LDL fractions. Niacin combination therapy raises HDL cholesterol and decreases dense LDL and IDL cholesterol levels. Changes in LDL and IDL are related to improvement in CVD. Lipoprotein subfraction analysis should be performed in larger studies utilizing niacin in combination with statins.

Background —Small, dense LDL particles are associated with coronary artery disease (CAD) and predict angiographic changes in response to lipid-lowering therapy. Intensive lipid-lowering therapy in the Familial Atherosclerosis Treatment Study (FATS) resulted in significant improvement in CAD. This study examines the relationship among LDL density, hepatic lipase (HL), and CAD progression, identifying a new biological mechanism for the favorable effects of lipid-altering therapy. Methods and Results —Eighty-eight of the subjects in FATS with documented coronary disease, apolipoprotein B levels ≥125 mg/dL, and family history of CAD were selected for this study. They were randomly assigned to receive lovastatin (40 mg/d) and colestipol (30 g/d), niacin (4 g/d) and colestipol, or conventional therapy with placebo alone or with colestipol in those with elevated LDL cholesterol levels. Plasma hepatic lipase (HL), lipoprotein lipase, and LDL density were measured when subjects were and were not receiving lipid-lowering therapy. LDL buoyancy increased with lovastatin-colestipol therapy (7.7%; P P P P P P P Conclusions —These studies support the hypothesis that therapy-associated changes in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-altering therapy to CAD improvement.

Lowering LDL cholesterol (LDL-C) levels to reduce or prevent coronary artery disease (CAD) progression and cardiac events in hypercholesterolemic subjects is now widely accepted. The clinical benefit of lowering LDL-C has recently been extended to individuals with normal or mildly elevated LDL-C. Recent analyses of large primary and secondary CAD prevention trials, however, clearly demonstrated that reducing LDL-C levels does not entirely account for the coronary event reduction associated with lipid-lowering therapy. Growing and compelling evidence is emerging on the role of triglyceride-rich lipoproteins (VLDL and IDL), high density lipoproteins (HDL), and small, dense LDL, as well as non lipid risk factors, in the regression or stabilization of atherosclerotic plaques of mild/moderate severity, which are associated with clinical cardiac events. Enzymes involved in the tight metabolic interrelationship between triglyceride-rich lipoproteins, small, dense LDL and HDL levels may represent potential therapeutic targets for CAD prevention by favourably altering lipoprotein composition and physical properties in addition to the current therapeutic focus on lipoprotein levels.

Patients in the original Familial Atherosclerosis Treatment Study (FATS) cohort were subgrouped into those with triglyceride levels ≤120 mg/dL (n = 26) and those with triglyceride levels ≥190 mg/dL (n = 40). Their therapeutic responses to niacin plus colestipol, lovastatin plus colestipol, colestipol alone, or placebo were determined. Therapeutic response was also determined in the same 2 triglyceride subgroups (n = 12 and n = 27, respectively) of patients selected for low levels of high-density lipoprotein (HDL) cholesterol and coronary artery disease. These triglyceride criteria were chosen to identify patient subgroups with high likelihood of “pattern A” (normal-size low-density lipoprotein [LDL] particles and triglyceride ≤120 mg/dL) or “pattern B” (small dense LDL and triglyceride ≥190 mg/dL). Our findings in these small patient subgroups are consistent with the emerging understanding that coronary artery disease patients presenting with high triglyceride levels have lower HDL-C, smaller less buoyant LDL-C, and greater very low-density lipoprotein (VLDL) cholesterol and VLDL apolipoprotein B, and are more responsive to therapy as assessed by an increase in HDL-C and reduction in triglycerides, VLDL-C, and VLDL apolipoprotein B. In the FATS high-triglyceride subgroup with these characteristics, a tendency toward greater therapeutic improvement in coronary stenosis severity was observed among those treated with either of the 2 forms of intensive cholesterol-lowering therapy. This improvement is associated with therapeutic reduction of LDL-C and elevation of HDL-C, but also appears to be associated with drug-induced improvement in LDL buoyancy.

We investigated the association between cholesterol across the LDL density range and in the VLDL and IDL particles with the prevalence of inflammatory cells in plaques of patients with severe carotid artery stenosis.Forty-five patients undergoing carotid endarterectomy were studied. Plaque specimens were analyzed for cellular composition by immunocytochemistry using monoclonal antibodies. Lipoprotein subclasses were separated by gradient ultracentrifugation.We found no correlations between LDL-C, HDL-C and plasma triglyceride levels with plaque cellular composition. On the other hand, macrophage content was significantly related to cholesterol in the dense LDL subclasses (r = 0.30, p0.01) and in the triglyceride-rich lipoprotein remnants, namely dense VLDL and IDL particles (r = 0.46, p0.01). HDL subclasses were not correlated with plaque cellular composition. In a mirror manner, smooth muscle cells were inversely associated with cholesterol levels of the dense LDL subclasses (r = -0.32, p0.01 fraction 10; r = -0.26, p0.05 fraction 11) while only a non-significant trend was observed with the cholesterol in the VLDL-IDL fractions. These results provide the pathophysiological background to account for the relevance of non-HDL-C as the only lipid parameter, aside LDL density, significantly associated (β = 0.351, p = 0.021) with carotid plaque macrophage content.We provide evidence that lipoprotein subclasses, specifically cholesterol in the dense LDL fractions and in the triglyceride-rich lipoprotein remnants, significantly affect carotid plaque cellular composition, in particular macrophages content.

Paraoxonase, an enzyme associated with the high density lipoprotein (HDL) particle, hydrolyzes paraoxon, the active metabolite of the insecticide parathion. Several studies have shown that paraoxonase levels in humans have a distribution characteristic of two alleles, one with low activity and the other with high activity. Paraoxonase also has arylesterase activity, which does not exhibit activity polymorphism and can therefore serve as an estimate of enzyme protein. Although the ability of paraoxon to irreversibly inhibit lipoprotein lipase (LPL) has been exploited experimentally for many years, the role of plasma paraoxonase in lipoprotein metabolism is unknown. Seventy-two normal individuals were examined for paraoxonase genotypes, plasma paraoxonase and arylesterase activities, postheparin LPL and hepatic lipase (HL) activities, and lipoprotein levels to determine whether (1) paraoxonase activity or genotype determines lipoprotein levels via an effect on LPL or HL activity or (2) variation in LPL and HL activities determines HDL levels and indirectly affects paraoxonase activity and protein levels in plasma. In the entire group, paraoxonase activity was related to arylesterase activity and genotype. Whereas arylesterase activity was correlated with HDL cholesterol (HDL-C) and apolipoproteinA-I (apoA-I) levels, neither arylesterase nor paraoxonase was correlated with LPL or HL activity. Furthermore, LPL activity was positively correlated and HL inversely correlated with HDL cholesterol and apoA-I levels, whereas LPL was inversely correlated with triglyceride levels. The paraoxonase genotypes of the study group were 30 individuals homozygous for the low-activity allele, 38 heterozygotes, and 4 individuals homozygous for the high-activity allele. Paraoxonase genotype accounted for ≈.75 of the variation in paraoxonase activity. Paraoxonase activity was linearly related to arylesterase activity within each subgroup. No difference in either LPL or HL activity was seen as a function of paraoxonase genotype, nor were differences seen in plasma triglyceride or HDL-C by genotype by ANOVA. The relation between LPL and HL and components of HDL in the paraoxonase genotypic subgroups in general reflected the associations seen in the group as a whole. Multivariate analysis showed that LPL, HL, and arylesterase, a measure of paraoxonase mass, were independent predictors of HDL cholesterol, while paraoxonase genotype or activity was not. Thus, variation in LPL and HL appears to be significantly related to HDL cholesterol and apoA-I levels. The levels of HDL are a major correlate of paraoxonase protein levels, while paraoxonase genotype is the major predictor of plasma paraoxonase activity.

A predominance of small LDL particles (subclass phenotype B), as determined by gradient-gel electrophoresis is found among patients with myocardial infarction. Despite physical differences in phenotype A and B particles, differences in lipid composition of particles in these phenotypes have yet to be reported in an unselected population of males and females. The present study used lipid/apoB ratios to analyze the amount of lipid per LDL particle, isolated by density-gradient ultracentrifugation, in 70 healthy subjects. Relative to apoB, the LDL particles from phenotype B subjects were found to contain less free cholesterol (0.391±0.05 versus 0.465±0.05; mean±SD; P P P P =NS) despite higher plasma triglyceride levels in the phenotype B subjects. LDL size and buoyancy were positively correlated with particle free cholesterol, phospholipid, and cholesteryl ester but not with particle triglyceride. These data suggest that the physical properties of LDL from subjects with phenotype A and B reflect their lipid composition. The compositional differences between LDL particles of the two phenotypes may provide new insight into the increased risk of myocardial infarction in subjects with small, dense LDL.

Background and Purpose— The object of our study was to compare the effect of high-dose vs low-dose atorvastatin vs nonstatin-based treatment (cholestyramine plus sitosterol) on cell composition of carotid plaque. Methods— We recruited 60 hypercholesterolemic patients (total cholesterol, 5.83–7.64 mmol/L) eligible for carotid endarterectomy. Three months before surgery, patients were randomized into 3 groups (n=20) receiving atorvastatin 10 mg/day (AT-10) or atorvastatin 80 mg/day (AT-80) or cholestyramine 8 g/day plus sitosterol 2.5 g/day. Analysis of cell composition was performed on endarterectomy specimens. Results— The 3 treatments resulted in a significant reduction of total cholesterol and low-density lipoprotein cholesterol (LDL-C), although the decrease in total cholesterol and LDL-C was of smaller magnitude in the cholestyramine plus sitosterol group. The 3 regimens did not influence the levels of inflammatory markers (including high-sensitivity C-reactive protein). Macrophage content was significantly lower in the AT-10 group plaques compared to the cholestyramine plus sitosterol group. It was further reduced in the AT-80 group plaques. These differences were no longer significant after adjustment for changes in LDL-C. No difference in lymphocyte number was observed among treatments, whereas the content of smooth muscle cells was higher in the AT- 80 group. An inverse association was observed between LDL-C changes in the 3 groups and macrophage content in the plaques. Conclusions— Short-term treatment with high-dose statin is superior to a nonstatin lipid-lowering regimen in reducing the macrophage cell content within atherosclerotic lesions, but this effect was determined by the degree of LDL-C–lowering.

Objective Apolipoprotein(a) [or apo(a)] isoform size, which is strongly genetically determined, showed significant association with the cardiovascular risk. Subjects on a fish diet have lower lipoprotein(a) levels, larger apo(a) isoform sizes and lower leptin levels than their vegetarian diet counterparts. We hypothesized that leptin may contribute to a potential association between the type of diet and the size of apo(a) isoforms. Methods Anthropometric data, dietary nutrients, lipoprotein profile, plasma leptin levels, and apo(a) isoforms were evaluated in two related homogenous African tribal populations of Tanzania, one on a primarily freshwater fish diet ( n =278), and the other on a vegetarian diet ( n =326). Results We observed a strong negative association between leptin levels and size of each of the apo(a) isoforms in both fish and vegetable diet groups, and in both genders. However, leptin was not associated with levels of lipoprotein(a). In multivariate analysis, a strong and independent association between leptin and size of apo(a) isoforms was observed. The size of apo(a) isoforms was strongly associated with high and low leptin states. Subjects with low leptins had 30% larger sizes of apo(a) isoforms than their high leptin counterparts. Conclusions High leptin subjects have smaller, potentially more atherogenic, apo(a) isoform sizes than low leptin ones. We suggest that omega-3 rich diet can influence the levels of apo(a) and/or Lp(a) even though they are mainly genetically determined. These findings may have implications for understanding the interaction between leptin and cardiovascular risk.

Objective The presence of small dense LDL has been associated with increased cardiovascular risk and with the progression of coronary and carotid atherosclerosis in case-control and prospective studies. The aim of this study was to investigate the relation between different lipoprotein subfractions with intima-media thickness of the common carotid artery in a free-living, healthy population, and to evaluate whether in patients with comparable LDL-C, the different lipoprotein subclasses differently affected the expression of chemokines, cytokines and adhesion molecules in peripheral blood mononuclear and endothelial cells. Methods and results The lipoprotein cholesterol profile and the LDL buoyancy (LDL-RF) were evaluated in a cohort of 156 healthy subjects randomly selected from the PLIC (Progressione Lesione Intimale Carotidea) study. The LDL-RF was directly and significantly correlated to weight, body mass index, waist, hip, waist/hip ratio, triglycerides, fasting glycemia and intima media thickness (IMT) of the common carotid artery and inversely related to HDL-C. After multivariate statistical analysis, IMT was independently associated with age, LDL-RF and HDL-C and among the lipoprotein subclasses, only those corresponding to triglyceride-rich lipoproteins (TGRL) and small dense LDL (sdLDL) independently predicted IMT variance. Peripheral blood mononuclear cells (PBMC) isolated from patients with the predominance of sdLDL (pattern B) had an increased mRNA expression of pro-inflammatory molecules compared to PBMC from patients with the predominance of large LDL (pattern A); in endothelial cells TGRL from pattern B subjects and much less those from pattern A induced the expression of pro-inflammatory genes while sdLDL from either pattern A or B subjects were less effective and showed comparable effects. Conclusion LDL-relative flotation rate significantly correlates with several cardiometabolic parameters. Furthermore cholesterol levels lipoprotein subfractions within the TGRL and sdLDL density range are independent predictors of IMT variance and are associated with a pro-inflammatory activation of PBMC and endothelial cells.

Despite achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure, and glycemia in accordance with current standards of care, patients with dyslipidemia remain at high residual risk of vascular events. Atherogenic dyslipidemia, characterized by elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease (CVD), type 2 diabetes mellitus, or metabolic syndrome and contributes to both macrovascular and microvascular residual risk. However, atherogenic dyslipidemia is largely underdiagnosed and undertreated in clinical practice. The Residual Risk Reduction Initiative (R3i) was established to address this highly relevant clinical issue. The aims of this position paper are (1) to highlight evidence that atherogenic dyslipidemia is associated with residual macrovascular and microvascular risk in patients at high risk for CVD, despite current standards of care for dyslipidemia and diabetes ; and (2) to recommend therapeutic intervention for reducing this residual vascular risk supported by evidence and expert consensus. Lifestyle modification with nutrition and exercise is an important, effective, and underutilized first step in reducing residual vascular risk. Therapeutic intervention aimed at achievement of all lipid targets is also often required. Combination lipid-modifying therapy, with the addition of niacin, a fibrate, or omega-3 fatty acids to statin therapy, increases the probability of achieving all lipid goals. Outcomes studies are in progress to evaluate whether these combination treatment strategies translate to a clinical benefit greater than that achieved with statins alone. The R3i highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual risk of CVD events and microvascular complications among patients with dyslipidemia receiving therapy for high levels of LDL cholesterol and for diabetes in accordance with current standards of care.

Statins lower cardiovascular risk in patients with diabetes; however, as these patients are at higher risk than other cardiovascular patients, statins merely decrease coronary event rates to the level seen in untreated nondiabetic individuals at risk for cardiovascular disease, indicating the existence of substantial residual risk. One reasonable explanation resides in the fact that statins have only limited effectiveness on hypertriglyceridemia and low HDL cholesterol, and they do not normalize the LDL size-distribution pattern. Peroxisome proliferator-activated receptor (PPAR)alpha agonists, which include fibrates, normalize this atherogenic lipid profile, as well as several cardiovascular risk markers associated with the metabolic syndrome and type 2 diabetes. In particular, hypertriglyceridemia and the ratio of small dense:large buoyant LDL particles are significantly improved. Outcome trials of PPARalpha agonists have demonstrated reductions in cardiovascular morbidity in patients with diabetes and in those with the metabolic syndrome; plaque progression is diminished, diabetic nephropathy and retinopathy are counteracted and amputation-risk decreased. The combination of fibrates with statins improves overall lipoprotein profile further. PPARalpha agonists seem particularly indicated in patients with diabetes who have residual dyslipidemia (high triglyceride and/or low HDL) despite receiving statin therapy, and patients who are nondiabetic, overweight, insulin-resistant and who have hypertriglyceridemia and/or low HDL cholesterol and chronic inflammation.

Clinical guidelines highlight the importance of dyslipidaemia management for reducing the risk of cardiovascular disease in patients with type 2 diabetes and metabolic syndrome. While statins represent the main focus of therapy, there is increasing evidence that the addition of a fibrate such as fenofibrate provides further reduction in risk. Fenofibrate also offers a number of benefits beyond lipid modification; these are mediated by peroxisome proliferator-activated receptor-alpha (PPARα) activation and appear to be independent of effects of glucose and lipid metabolism. Furthermore, as shown by the Fenofibrate Intervention for Event Lowering in Diabetes (FIELD) study, fenofibrate treatment has promising effects in preventing progression of diabetes-related microvascular complications. PPARα is critical to lipid metabolism in the liver. Recent findings which showed that pioglitazone, a PPARγ agonist with weak PPARα activity, improved fatty liver disease in patients with non-alcoholic steatohepatitis (NASH) and metabolic syndrome or type 2 diabetes have prompted interest in whether more potent PPARα agonists, such as fenofibrate, may have a role in the management of non-alcoholic fatty liver disease (NAFLD). The combination of fenofibrate and a statin is well tolerated, with no apparent increase in the risk of myopathy, unlike gemfibrozil-statin combination therapy. In overview, the available evidence indicates that the combination of fenofibrate with a statin is a useful approach for optimising reduction in the risk of cardiovascular disease in patients with type 2 diabetes and metabolic syndrome, as well as delaying the progression of diabetes-related microvascular complications. Data are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study to evaluate the outcome benefits of this approach.

Abdominal obesity and insulin resistance are very rarely found in isolation: most of the time they are associated with a cluster of other parameters or metabolic factors. These include dyslipidaemia, raised blood pressure, glucose and other factors which may be measured only in the research setting (such as interleukin-6 [IL-6]); each of these components per se is a risk factor for cardiovascular disease. Since several of them cluster in type 2 diabetes, it is no surprise that type 2 diabetes patients are at considerably higher risk for cardiovascular disease compared to people without diabetes. Diabetes Vasc Dis Res 2007;4(suppl 2):S12‐S16 doi:10.3132/dvdr.2007.020 Some of these risk factors belong to the list of variables evaluated in the INTERHEART study, which reviewed data from 52 countries worldwide and multiple ethnic groups. 1 Table 1 reveals that apolipoprotein B (apoB), smoking, diabetes, abdominal obesity and hypertension form part of the list that accounts for 90% of the risk of developing heart disease. Thus, the traditional risk factors still account for the majority of heart disease throughout the world across different ethnic groups. Two thirds of patients with type 2 diabetes die from coronary heart disease, other forms of heart disease such as heart failure or cerebrovascular disease. Diabetes increases 2‐4fold the risk of cardiovascular disease and doubles the risk of stroke. 2

The common -514 C-T promoter polymorphism of the hepatic lipase gene (LIPC) and the cholesteryl ester transfer protein (CETP) gene TaqIB polymorphism affect atherogenesis. We investigated the potential relationship between these polymorphisms and the maximum-intima-media thickness (M-IMT) after carotid endarterectomy.The LIPC and CETP genotypes were determined by PCR in 68 patients undergoing endarterectomy. Plaque specimens were analysed for cell composition by immunocytochemistry. Six month after surgery the M-IMT of the revascularized vessel was assessed by B-mode ultrasonography.The CC carriers had denser LDL particles (p0.0005), an abundance of macrophages (p0.0005), fewer SMCs in the carotid plaque (p0.0005), and higher prevalence of cerebrovascular events (72% versus 28%, p=0.002) compared to CT/TT carriers. After endarterectomy, CC carriers showed a lower M-IMT than the CT/TT group (1.36 mm versus 1.76 mm, p=0.04). No association between the CETP polymorphism and either carotid plaque cellular composition or M-IMT was observed. In a multivariate analysis, M-IMT was associated with plaque cell composition (macrophages, r=-0.39; SMC, r=0.44; p0.005 for both) but not with pre-operative LDL-C, HDL-C, triglycerides, or LDL density.The LIPC promoter -514 C-T polymorphism is associated with a significantly reduced development of neointima after surgery. This effect seems to be mediated by scarcity of SMC in the plaque of CC carriers who display an excess prevalence of cerebrovascular events prior endarterectomy but are at low risk for restenosis. The pre-operative lipid phenotype plays a marginal role in the neointima formation.

Recent advances in basic science have shown that atherosclerosis should be considered as a chronic inflammatory process, and that a pivotal role of inflammation is evident from initiation through progression and complication of atherosclerosis. In the past few years many studies have examined the potential for biochemical markers of inflammation to act as predictors of coronary heart disease (CHD) risk in a variety of clinical settings. Several large, prospective epidemiological studies have shown consistently that C-reactive protein (CRP) and interleukin-6 (IL-6) plasma levels are strong independent predictors of risk of future cardiovascular events, both in patients with a history of CHD and in apparently healthy subjects. These molecules could be useful to complement traditional risk factors, as well as to identify new categories of subjects prone to atherosclerosis development. An intriguing question is whether these inflammatory molecules simply represent sensitive markers of systemic inflammation or if they actively contribute to atherosclerotic lesion formation and instability. In this paper we will review the evidence concerning the cardiovascular prognostic value and the potential direct involvement of CRP and IL-6 in atherogenesis.