Search

Background: The level of blood lipid is closely related to prognosis in cardiovascular diseases. This study aims to analyze the effect of serum low-density lipoprotein cholesterol (LDL-C) levels on the long-term mortality in acute aortic dissection (AAD). A lower admission LDL-C level is associated with an increased risk of long-term mortality in AAD., Methods: We analyzed the data of 284 patients with AAD admitted to the First Affiliated Hospital of Shantou University Medical College from February 2016 to September 2019. Patients were followed up post-discharge. All patients were divided into either an LDL-C low-level group or an LDL-C high-level group according to the optimal cut-off point obtained by the receiver operating characteristic (ROC) curve. The endpoint outcome was long-term mortality in AAD. A survival analysis and Cox proportional hazards model were used., Results: According to the Youden index, the optimal cut-off point for LDL-C was 2.755 mmol/L. The Kaplan-Meier survival analysis curves showed that the long-term mortality of the LDL-C low-level group (<2.755 mmol/L) was significantly higher than that of the LDL-C high-level group (≥2.755 mmol/L) (log-rank χ 2 =13.912, P<0.001). After multivariate Cox regression analysis, LDL-C <2.755 mmol/L was still significantly associated with long-term mortality in AAD (HR=3.287, 95% CI: 1.637-6.600, P=0.001). In addition, cystatin C was also an independent risk factor for the long-term prognosis of AAD (HR=1.253, 95% CI: 1.057-1.486, P=0.009)., Conclusions: A lower admission LDL-C level may be associated with an increased risk of long-term mortality in AAD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-3511). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Lowering low-density lipoprotein cholesterol (LDL-C) levels using a statin is a cornerstone of preventive therapeutic management following acute myocardial infarction (AMI). In addition to its anti-atherosclerotic effects, recent studies reported a lower occurrence of heart failure (HF) under statin therapy. However, there is a wide variability in statin response. The association between the response to statin and the occurrence of HF in AMI subjects remains unclear. The purpose of present study is to examine whether the variability in statin response affects HF risk after AMI., Methods: We analyzed 505 statin-naïve AMI subjects undergoing primary percutaneous coronary intervention (PCI) who commenced atorvastatin, rosuvastatin, or pitavastatin. Statin hyporesponse was defined as a reduction in LDL-C levels <15% from baseline to 1 month after statin therapy. HF outcomes were compared between patients with and without statin hyporesponse., Results: Statin hyporesponse was identified in 15.2% (77/505) of study subjects. During a median 4.4-year observational period, statin hyporesponse was associated with a greater likelihood of HF [hazard ratio (HR) =3.01, 95% confidence interval (CI): 1.27-6.79, P=0.01]. This increased HF risk in statin hyporesponders was consistently observed in a multivariate Cox proportional hazards model (HR =2.74, 95% CI: 1.01-6.75, P=0.04), a propensity score-matched cohort (HR =12.30, 95% CI: 1.50-100.3, P=0.01) and in an inverse probability of treatment weights analysis with average treatment effects (coefficient =7.02, 95% CI: 2.29-21.58, P=0.0006)., Conclusions: Hyporesponse to statins increases HF risk after AMI. Our findings highlight statin hyporesponse as a high-risk feature associated with HF events., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-415). YK serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from Jul 2019 to Jun 2021. The other author has no conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Introduction : Although statin therapy is a powerful lipid-lowering strategy, only one-fifth of statin users currently reach their lipid goals. In addition, statin treatment alone has relatively low efficacy in reducing other lipid fractions than low-density lipoprotein-cholesterol (LDL-C). In such cases, most guidelines recommend adding the cholesterol absorption inhibitor ezetimibe. Areas covered : This paper summarizes the main pharmacological characteristics of rosuvastatin and ezetimibe (mechanism of action, metabolism), their lipid-lowering and pleiotropic effects, with particular attention to the clinical effects of the combined drugs in hypercholesterolemia and mixed dyslipidemia patients (such as the ones affected by diabetes mellitus and Acquired Immune Deficiency Syndrome (AIDS)). Expert opinion : The additive effect of rosuvastatin and ezetimibe helps to reach lipid goals in a large number of high-risk patients, while avoiding some safety issues related to high dosages of intensive statin therapy. Patients with diabetes receive additional benefits from ezetimibe as they seem to absorb cholesterol more effectively than non-diabetic ones, because of increased NPC1L1 gene expression. Ezetimibe augments rosuvastatin triglyceride-lowering and anti-inflammatory effects, as well. Taking into account its excellent safety profile and lack of clinically relevant drug-drug interactions, the rosuvastatin/ezetimibe association is a valuable alternative to statin dose uptitration.

Background: Clinical practice guidelines (CPGs) provide many recommendations for hyperlipidemia management, but some of them are still debatable., Methods: We applied the six-domain Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument to evaluate the quality of guidelines with lipid management recommendations for coronary heart disease (CHD), including dyslipidemia and CHD guidelines published from 2009 to 2019. Meanwhile, we synthesized and compared major recommendations and present the consistency and controversy in current dyslipidemia management., Results: Among 19 guidelines included, ten guidelines ("strongly recommended" with AGREE scores 61-94%) performed better than the other nine (38-65% as "recommended with some modification") For blood lipid tests, most CHD guidelines simply required fasting sample while dyslipidemia guidelines preferred non-fasting sample except in high triglycerides state. Most guidelines consistently chose low-density lipoprotein cholesterol (LDL-C) as the primary lipid-lowering target (LLT), while non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B were mainly selected as secondary LLTs. The specific goals of LDL-C lowering were either to lower than 70 mg/dL or with at least 50% reduction. All guidelines recommended high intensity or maximally tolerable doses of statins, while ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recommended as second-line therapy., Conclusions: The general quality of guidelines for lipid management is satisfactory. Consensus has been reached on the specific goal of lipid reduction and the intensity of statins therapy. Further research is needed to validate the application of non-fasting sample and non-HDL-C target, as well as the efficacy and safety of ezetimibe and PCSK9 inhibitors., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Adipose tissue, an endocrine organ, secretes bioactive factors including adiponectin. Adiponectin is a protein hormone that enhances insulin sensitivity through increased fatty acid oxidation and inhibition of hepatic glucose production. We assessed the association of the adiponectin promoter region polymorphisms -11391 G/A and -11377 C/G with susceptibility to type 1 (T1DM) and type 2 (T2DM) diabetes mellitus in the population of west Iran. Also, we investigated the effect of adiponectin level and lipid profile on T1DM and T2DM development. In this case-control study, we recruited 189 patients with diabetes (100 T2DM and 89 T1DM) and 161 sex and age-matched unrelated healthy controls. Adiponectin mutations were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the protein level was measured by the enzyme-linked immunosorbent assay. Other biochemical parameters were determined by routine laboratory methods. The G allele of adiponectin gene at -11377 position (C/G) significantly increased the risk of T1DM. With respect to genotype models, codominant (2.97 times), dominant (3.6-fold), and over-codominant (2.9-fold) patients with T1DM who carried -11377 C > G single-nucleotide polymorphisms were significantly susceptible to the development of the disease. A significantly higher level of adiponectin in T1DM was oberved compared with the control group. In contrast, patients with T2DM had lower adiponectin levels compared with healthy controls. The genotype distributions of -11391 G/A polymorphisms were the same for patients with diabetes and control groups. The presence of G allele at -11377 C/G adiponectin gene significantly increased serum adiponectin level and may be a risk factor for T1DM susceptibility among the western Iranian population., (© 2018 Wiley Periodicals, Inc.)

Background: The serum lipid profile, including LDL-C level, is associated with hypertension which is the major cause of cerebrovascular disease (CVD) amounting 30% of global death rate. Previous work also demonstrated important roles of genetic variants of SLC12A3 gene on human CVD, hypertension and other diseases in Mongolian population. However, the relationship between SLC12A3 gene polymorphisms on individuals' lipid profile is still unknown. Methods: A panel of 15 SNPs of SLC12A3 gene was genotyped within a 424 Mongolians pedigree cohort. The associations between SLC12A3 polymorphisms and four lipid profiles were analyzed by family-based association test (FBAT) and confirmed with haplotype analysis. Results: From both single site and haplotype analyses, the results demonstrated a close relationship between SLC12A3 polymorphisms and LDL-C level. Two SNPs, rs5803 and rs711746 showed significant associations with individuals' serum LDL-C level (z = − 2.08, P-e = 0.038; z = 2.09, P-e = 0.023, respectively), and distribution of haplotypes constructed by two SNPs also associated with participants' serum LDL-C level, significantly (Global Chi2 = 9.06 df = 3, P = 0.028). Conclusion: Our results demonstrated the importance of SLC12A3 polymorphisms in individuals' difference about their serum lipid profiles, thereby providing evidence that the genetic variants may contribute to CVD development via modulating person's LDL-C level and blood pressure, in certain contexts. [ABSTRACT FROM AUTHOR]

Objective: To observe the effects of herbal-cake-separated moxibustion on the repair of damaged vascular endothelium structure and the content of stromal cells derived factor 1 (SDF-1) in rabbits with atherosclerosis., Methods: A total of 75 rabbits were randomly divided into a normal group, a model group, a direct moxibustion group, an atorvastatin calcium group and a herbal-cake-separated moxibustion group, 15 rabbits in each one. The rabbits in the normal group were fed with normal diet, and the remaining rabbits were fed with high-cholesterol diet for 12 weeks to prepare atherosclerotic model. Two groups of acupoints, one was "Juque" (CV 14), "Tianshu" (ST 25) and "Fenglong" (ST 40), the other one was "Xinshu" (BL 15), "Ganshu" (BL 18) and "Pishu" (BL 20), were applied in the direct moxibustion group and herbal-cake-separated moxibustion group; the two groups of acupoints were selected alternatively every other day. The moxibustion was given for 30 min per treatment, once a day for 4 weeks. The rabbits in the atorvastatin calcium group were treated with atorvastatin calcium tablets (1.96 mg•kg -1 •d -1 ) which were crushed into powder and mixed into breakfast. After modeling, the rabbits in the normal group and model group received no treatment, and immobilized at the time when moxibustion was applied in other three groups. The levels of total cholesterol (TC) and triglyceride (TG) were measured by enzymic method; the low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured by colorimetric method; the morphological structure of aortic wall was observed under optical microscope; the serum level of SDF-1 was determined by enzyme-linked immunosorbent assay (ELISA)., Results: After treatment, compared with the normal group, the levels of TC, TG and LDL-C were significantly increased in the model group (all P <0.01), and the level of HDL-C was decreased ( P <0.01). Compared with the model group, the levels of TC, TG and LDL-C were significantly decreased (all P <0.01), and the level of HDL-C was significantly increased in the direct moxibustion group, atorvastatin calcium group and herbal-cake-separated moxibustion group ( P <0.01, P <0.05). Compared with the normal group, the morphological structure of aortic wall was significantly damaged in the model group. Compared with the model group, the vascular endothelial structure was improved in the atorvastatin calcium group and herbal-cake-separated moxibustion group, and the pathological change of aorta endothelial in the direct moxibustion group was relieved. After treatment, compared with the model group, the level of SDF-1 was increased in the direct moxibustion group, atorvastatin calcium group and herbal-cake-separated moxibustion group ( P <0.05, P <0.01); the level of SDF-1 in the herbal-cake- separated moxibustion group was higher than that in the direct moxibustion group ( P <0.05)., Conclusion: The herbal- cake-separated moxibustion can promote the expression of SDF-1 in serum and repair the damaged aortic endothelial structure.

Statins are currently the major therapeutic strategies to lower low-density lipoprotein cholesterol (LDL-C) levels. However, a number of hypercholesterolemia patients still have a residual cardiovascular disease (CVD) risk despite taking the maximum-tolerated dose of statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein receptor (LDLR), inducing its degradation in the lysosome and inhibiting LDLR recirculating to the cell membranes. The gain-offunction mutations in PCSK9 elevate the LDL-C levels in plasma. Therefore, PCSK9 inhibitors become novel therapeutic approaches in the treatment of hypercholesterolemia. Several PCSK9 inhibitors have been under investigation, and much progress has been made in clinical trials, especially for monoclonal antibodies (MoAbs). Two MoAbs, evolocumab and alirocumab, are now in clinical use. In this review, we summarize the development of PCSK9 inhibitors, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), small molecule inhibitor, MoAbs, mimetic peptides and adnectins, and the related safety issues., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy., Methods: We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis., Results: New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis., Conclusion: PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background Low-density lipoprotein particle (LDL-P) has recently been found to be a stronger predictor of cardiovascular disease (CVD) than LDL-cholesterol (LDL-C). Objectives Whether LDL-P is associated with subclinical atherosclerosis, independent of LDL-C, as well as other lipid measures has not been fully examined. We aimed to analyze LDL-P associations with measures of subclinical atherosclerosis. Methods We examined 870 Japanese men randomly selected from Kusatsu City, Shiga, Japan, aged 40–79 years from 2006–2008, free of clinical CVD and not using lipid-lowering medication. Cross-sectional associations of lipid measures with carotid intima-media thickness (cIMT) and coronary artery calcification (CAC; >0 Agatston score) were examined. Results LDL-P was significantly positively associated with cIMT and maintained this association after adjustments for LDL-C and other lipid measures. Although these lipid measures were positively associated with cIMT, model adjustment for LDL-P removed any significant relationships. Higher LDL-P was associated with a significantly higher odds ratio of CAC and further adjustment for LDL-C did not affect this relationship. In contrast, the LDL-C association with CAC was no longer significant after adjustment for LDL-P. Other lipid measures attenuated associations of LDL-P with CAC. Likewise, associations of these measures with CAC were attenuated when model adjustments for LDL-P were made. Conclusions In a community-based sample of Japanese men, free of clinical CVD, LDL-P was a robust marker for subclinical atherosclerosis, independent of LDL-C and other lipid measures. Associations of LDL-C and other lipid measures with either cIMT or CAC were generally not independent of LDL-P. [ABSTRACT FROM AUTHOR]

Background: Dyslipidaemia is a risk factor for macrovascular complications in patients with type 2 diabetes mellitus (T2DM). Our aim was to assess the use of lipid lowering drugs (LLDs) in patients with T2DM and co-existing dyslipidaemia., Method: A multicentre, non-interventional survey conducted in 6 Middle Eastern countries (Bahrain, Oman, Qatar, United Arab Emirates, Kingdom of Saudi Arabia and Kuwait). Patients with T2DM (n = 3338) taking LLD treatment for ≥3 months with no dose change for ≥6 weeks were enrolled., Results: The mean age (SD) of T2DM patients was 56.6 ±10.6 years; the majority (99%) were on statin monotherapy. Only 48% of these patients achieved their low density lipoprotein cholesterol (LDL-C) goal and 67.7% of the patients had a high cardiovascular disease (CVD) risk according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines. Of those who achieved LDL-C goals (n=1589), approximately one-third were at very high CVD risk and the patients who had received statin monotherapy showed the highest proportion in LDL-C goal attainment, followed by those treated with fibrate monotherapy. In a multivariate logistic regression model, taking drugs daily (odds ratio, OR: 1.64, 95% CI 1.25, 2.15) and older age (OR: 1.09, 95% CI 1.01, 1.18) were significantly associated with better odds of attaining LDL-C target. In contrast, patients with higher levels of ApoA1 (OR: 0.73, 95% CI [0.67,0.79]), Metabolic Syndrome (OR: 0.64, 95% CI [0.53, 0.76]), higher CV risk (OR: 0.33, 95% CI 0.27, 0.41), those who forgot to take their medication (OR: 0.74, 95% CI 0.62,0.88) and those who stopped taking medication when cholesterol became normal (OR: 0.67, 95% CI 0.55,0.82) were significantly associated with lower odds of attaining LDL-C target., Conclusion: The results of this study highlight the suboptimal management of dyslipidaemia in T2DM patients at high and very high risk of CVD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) levels, contributes substantially to the development of coronary artery disease and the risk for cardiovascular events. As the first-line pharmacotherapy, statins have been shown to reduce both LDL-C levels and cardiovascular events. However, despite intensive statin therapy, a sizable proportion of statin-treated patients are unable to achieve the recommended target LDL-C levels, and not all patients can avoid future cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis by enhancing the degradation of hepatic low-density lipoprotein receptor (LDLR). Owing to its importance in lipid metabolism, PCSK9 has emerged as a novel pharmacological target for lowering LDL-C levels. In this review, the potential role of circulating PCSK9 as a new biomarker of lipid metabolism is described. Next, previous studies evaluating the effects of lipid-modifying pharmacological agents, particularly statins, on circulating PCSK9 concentrations are summarized. Statins decrease hepatic intracellular cholesterol, resulting in increased LDLRs as well as increased PCSK9 protein. There is a clear dose-response effect of statin treatment on PCSK9 level, as increasing doses of statins also increase the level of circulating PCSK9. Finally, the available therapeutic strategies to inhibit PCSK9 are present. Monoclonal antibodies against PCSK9, in combination with statins, are one of the most promising and novel approaches to achieve further reduction of LDL-C levels and reduce the risk of cardiovascular events.

Aim: To estimate real-world cardiovascular disease (CVD) burden and value-based price range of evolocumab for a US-context, high-risk, secondary-prevention population., Materials and Methods: Burden of CVD was assessed using the UK-based Clinical Practice Research Datalink (CPRD) in order to capture complete CV burden including CV mortality. Patients on standard of care (SOC; high-intensity statins) in CPRD were selected based on eligibility criteria of FOURIER, a phase 3 CV outcomes trial of evolocumab, and categorized into four cohorts: high-risk prevalent atherosclerotic CVD (ASCVD) cohort (n = 1448), acute coronary syndrome (ACS) (n = 602), ischemic stroke (IS) (n = 151), and heart failure (HF) (n = 291) incident cohorts. The value-based price range for evolocumab was assessed using a previously published economic model. The model incorporated CPRD CV event rates and considered CV event reduction rate ratios per 1 mmol/L reduction in low-density lipoprotein-cholesterol (LDL-C) from a meta-analysis of statin trials by the Cholesterol Treatment Trialists Collaboration (CTTC), i.e. CTTC relationship., Results: Multiple-event rates of composite CV events (ACS, IS, or coronary revascularization) per 100 patient-years were 12.3 for the high-risk prevalent ASCVD cohort, and 25.7, 13.3, and 23.3, respectively, for incident ACS, IS, and HF cohorts. Approximately one-half (42%) of the high-risk ASCVD patients with a new CV event during follow-up had a subsequent CV event. Combining these real-world event rates and the CTTC relationship in the economic model, the value-based price range (credible interval) under a willingness-to-pay threshold of $150,000/quality-adjusted life-year gained for evolocumab was $11,990 ($9,341-$14,833) to $16,856 ($12,903-$20,678) in ASCVD patients with baseline LDL-C levels ≥70 mg/dL and ≥100 mg/dL, respectively., Conclusion: Real-world CVD burden is substantial. Using the observed CVD burden in CPRD and the CTTC relationship, the cost-effectiveness analysis showed that, accounting for uncertainties, the expected value-based price for evolocumab is higher than its current annual cost, as long as the payer discount off list price is greater than 20%.

Examination of the current the American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on the prevention of cardiovascular disease and the management of dyslipidemias finds much common ground. Both note that Atherosclerotic cardiovascular disease (ASCVD) is, in most people, the product of a number of risk factors, notably tobacco exposure, hyperlipidemia, hypertension, inactivity, overweight and diabetes. They stress that risk calculators can help in the assessment of risk in apparently healthy persons. Persons with established ASCVD and many with diabetes or renal impairment are at high to very high risk and warrant intensive risk factor advice and guideline-based preventive therapies. The ACC/AHA guidelines favor the universal use of statins in all high-risk subjects and in primary prevention where the global risk exceeds 7.5% in 10 years, with a percentage reduction in low-density lipoprotein cholesterol (LDL-C) based on statin intensity as the "goal". In contrast, the ESC/EAS guidelines favor a goal or percentage-based reduction in LDL-C based on total risk and baseline LDL-C level. Both guidelines consider certain imaging and other measures to stratify risk as well as the use of non-statin therapies in those not achieving recommended targets. Perhaps the most important challenges are to stress similarities rather than differences, and to simplify communications with both healthcare professionals and the public., Competing Interests: Conflicts of Interest: IM Graham has received speaker fees confined to talks on the content of the guidelines and on risk estimation from MSD and Pfizer. AL Catapano has received speaker/consulting fees from Aegerion, Abbot, Amgen, BMS, Eli Lilly, Genzyme, Kowa, Merck, Novartis, Pfizer, Recordati, Roche, Sanofi and Sigma-Tau. ND Wong has received research support thorough his institution from Amgen, Regneron and Gilead, and speaker/consulting fees from Amgen, Merck, Pfizer, Sanofi and Regeneron.

Background: In 2014, guidelines from the National Institute for Health and Care Excellence (NICE) provided updated recommendations on lipid-modifying therapy (LMT). We assessed clinical practice contemporaneous to release of these guidelines in a UK general practice setting for secondary and high-risk primary-prevention populations, and extrapolated the findings to UK nation level., Methods: Patients from The Health Improvement Network database with the following criteria were included: lipid profile in 2014 (index date); ≥20 years of age; ≥2 years representation in database prior to index; ≥1 statin indication either for atherosclerotic cardiovascular disease (ASCVD) or the non-ASCVD conditions high-risk diabetes mellitus and/or chronic kidney disease., Results: Overall, 183 565 patients met the inclusion criteria (n=91 479 for ASCVD, 92 086 for non-ASCVD). In those with ASCVD, 79% received statin treatment and 31% received high-intensity statin. In the non-ASCVD group, 62% were on a statin and 57% received medium-intensity or high-intensity statin. In the ASCVD and non-ASCVD cohorts, 6% and 15%, respectively, were already treated according to dosing recommendations as per updated NICE guidelines. Extrapolation to the 2014 UK population indicated that, of the 3.3 million individuals with ASCVD, 2.4 million would require statin uptitration and 680 000 would require statin initiation (31% de novo initiation, 60% reinitiation, 9% addition to non-statin LMT) to achieve full concordance with updated guidelines. Of the 3.5 million high-risk non-ASCVD individuals, 1.6 million would require statin uptitration and 1.4 million would require statin initiation (59% de novo initiation, 36% reinitiation, 5% addition to non-statin LMT)., Conclusions: A large proportion of UK individuals with ASCVD and high-risk non-ASCVD received statin treatment (79% and 62%, respectively) during the year of NICE 2014 guidelines release. Up to 94% of patients with ASCVD and 85% of high-risk non-ASCVD individuals, representing ∼3 million individuals in each group, would require statin uptitration or initiation to achieve full concordance with updated guidelines., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The prevalence of atherosclerotic cardiovascular diseases (ASCVDs) is increasing globally and they have become the leading cause of death in most countries. Numerous experimental and clinical studies have been conducted to identify major risk factors and effective control strategies for ASCVDs. The development of imaging modalities with the ability to determine the plaque composition enables us to further identify high-risk plaque and evaluate the effectiveness of different treatment strategies. While intensive lipid-lowering by statins can stabilize or even regress plaque by various mechanisms, such as the reduction of lipid accumulation in a necrotic lipid core, the reduction of inflammation, and improvement of endothelial function, there are still considerable residual risks that need to be understood. We reviewed important findings regarding plaque vulnerability and some encouraging emerging approaches for plaque stabilization.

The atheroprotective role of high-density lipoprotein cholesterol (HDL-C) in cardiovascular disease has been unequivocally established, and epidemiological data have clearly demonstrated a strong inverse relationship between HDL-C levels and the risk of cardiovascular events, which is independent of the low-density lipoprotein cholesterol (LDL-C) levels. Thus, it would be logical to hypothesize that raising HDL-C might potentially lead to a reduction of cardiovascular risk. Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from HDL to very low-density lipoprotein and LDL. Therefore, CETP inhibition raises HDL-C levels and decreases LDL-C levels. The first trials with CETP inhibitors failed to show a reduction in cardiovascular events. However, newer CETP inhibitors with more favorable effects on lipids are presently being tested in clinical trials with the hope that their use may lead to a reduction in cardiovascular risk. This review aims to provide the current evidence regarding CETP inhibition, as well as the clinical and scientific data pertaining to the new CETP inhibitors in development.

This review discusses the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults and compares it with the 2014 National Lipid Association (NLA) Recommendations for Patient-Centered Management of Dyslipidemia. The review discusses some of the distinctions between the guidelines, including how to determine a patient's atherosclerotic cardiovascular disease risk, the role of lipoprotein treatment targets, the importance of moderate- and high-intensity statin therapy, and the use of nonstatin therapy in light of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To examine whether longitudinal changes in relative weight category (as indicated by change in body mass index [BMI] classification group) were associated with changes in nuclear magnetic resonance (NMR)−derived lipoprotein particles among US youth. Study design: Secondary analysis of data from a clustered randomized controlled trial. BMI and fasting blood samples were obtained from 2069 participants at the start of the 6th grade and end of the 8th grade. BMI was categorized as normal weight, overweight, or obese at both time points. Lipoprotein particle profiles were measured with NMR spectroscopy at both time points. Regression models were used to examine changes in relative weight group and change in lipoprotein variables. Results: A total of 38% of participants changed relative weight category (BMI group) during the 2.5-year study period. Low-density lipoprotein (LDL) cholesterol and non−high-density lipoprotein (HDL) cholesterol decreased almost universally, but more with improved BMI category. There were adverse effects on LDL size and total LDL particles, HDL size, and cholesterol for participants who remained obese or whose relative weight group worsened. Changes in relative category had no impact on HDL particles. Conclusion: Improvement in relative weight group from 6th to 8th grade was associated with favorable changes in non-HDL cholesterol, very low-density lipoprotein size, LDL size, HDL size, and LDL particles but had no effect on HDL particles. Findings indicate that an improvement in relative weight group between 6th and 8th grade had an effect on NMR-derived particles sizes and concentrations among a large group of adolescents, which overrepresented low-income minorities. [Copyright &y& Elsevier]

Background & Aims: Little is known about the effects of the vitamin D receptor (VDR) on hepatic activity of human cholesterol 7α-hydroxylase (CYP7A1) and cholesterol metabolism. We studied these processes in mice in vivo and mouse and human hepatocytes. Methods: Farnesoid X receptor (Fxr) −/− , small heterodimer partner (Shp) −/− , and C57BL/6 (wild-type control) mice were fed normal or Western diets for 3 weeks and were then given intraperitoneal injections of vehicle (corn oil) or 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3; 4 doses, 2.5 μg/kg, every other day). Plasma and tissue samples were collected and levels of Vdr, Shp, Cyp7a1, Cyp24a1, and rodent fibroblast growth factor (Fgf) 15 expression, as well as levels of cholesterol, were measured. We studied the regulation of Shp by Vdr using reporter and mobility shift assays in transfected human embryonic kidney 293 cells, quantitative polymerase chain reaction with mouse tissues and mouse and human hepatocytes, and chromatin immunoprecipitation assays with mouse liver. Results: We first confirmed the presence of Vdr mRNA and protein expression in livers of mice. In mice fed normal diets and given injections of 1,25(OH)2D3, liver and plasma concentrations of 1,25(OH)2D3 increased and decreased in unison. Changes in hepatic Cyp7a1 messenger RNA (mRNA) correlated with those of Cyp24a1 (a Vdr target gene) and inversely with Shp mRNA, but not ileal Fgf15 mRNA. Similarly, incubation with 1,25(OH)2D3 increased levels of Cyp24a1/CYP24A1 and Cyp7a1/CYP7A1 mRNA in mouse and human hepatocytes, and reduced levels of Shp mRNA in mouse hepatocytes. In Fxr −/− and wild-type mice with hypercholesterolemia, injection of 1,25(OH)2D3 consistently reduced levels of plasma and liver cholesterol and Shp mRNA, and increased hepatic Cyp7a1 mRNA and protein; these changes were not observed in Shp −/− mice given 1,25(OH)2D3 and fed Western diets. Truncation of the human small heterodimer partner (SHP) promoter and deletion analyses revealed VDR-dependent inhibition of SHP, and mobility shift assays showed direct binding of VDR to enhancer regions of SHP. In addition, chromatin immunoprecipitation analysis of livers from mice showed that injection of 1,25(OH)2D3 increased recruitment of Vdr and rodent retinoid X receptor to the Shp promoter. Conclusions: Activation of the VDR represses hepatic SHP to increase levels of mouse and human CYP7A1 and reduce cholesterol. [Copyright &y& Elsevier]

Background & Aims: Liver disease has been associated with cardiovascular disorders, but little is known about the relationship between serum levels of alanine aminotransferase (ALT) and markers of atherogenesis. We investigated the relationship between low–normal and high–normal levels of ALT and an extended panel of cardiovascular risk factors among individuals with no known diseases in a primary care setting. Methods: We performed a retrospective analysis of data collected from 6442 asymptomatic patients at wellness visits to a primary care setting in central Virginia from 2010 through 2011. Serum levels of ALT were compared with levels of lipids and lipoproteins, as well as metabolic, inflammatory, and coagulation-related factors associated with risk for cardiovascular disease. Results: Serum levels of ALT were higher than 40 IU/L in 12% of subjects, and in the high–normal range (19–40 IU/L in women and 31–40 IU/L in men) in 25% of subjects. ALT level was associated with the apolipoprotein B level, concentration and particle size of very-low-density lipoproteins, concentration of low-density lipoprotein (LDL) particles (LDL-P), and percentages of small dense LDL (sdLDL) and sdLDL-cholesterol (sdLDL-C) (P < .0001 for all). A high–normal level of ALT was associated with higher levels of LDL-C, LDL-P, sdLDL-C, and sdLDL particles (P < .001 for all). These effects were independent of age, body mass index, and hyperinsulinemia. Increasing levels of ALT and fasting hyperinsulinemia (>12 μU/mL) synergized with increasing levels of triglycerides, very-low-density lipoprotein particles, LDL-P, sdLDL-C, and percentage of sdLDL-C. Levels of APOA1, high-density lipoprotein-cholesterol, and high-density lipoprotein-class 2 were associated inversely with serum level of ALT (P < .0001 for all). Conclusions: In an analysis of asymptomatic individuals, increased serum levels of ALT (even high–normal levels) are associated with markers of cardiovascular disease. [Copyright &y& Elsevier]

Objectives: To characterize lipids and lipoproteins in a diverse school-based cohort and identify features associated with discordance between low-density lipoprotein cholesterol (LDL-C) and LDL particle (LDL-P). Study design: Sixth-grade children enrolled in the HEALTHY trial (n = 2384; mean age 11.3 ± 0.6 years; 54.2% female) were evaluated for standard lipids, lipoprotein particles measured by nuclear magnetic resonance, and homeostatic model of insulin resistance. Characteristics of subgroups with values of LDL-C and LDL-P discordant by >20 percentile units, an amount reasoned to be clinically significant, were compared. Results: Four-hundred twenty-eight (18%) of children were in the LDL-P < LDL-C subgroup and 375 (16%) in the LDL-P > LDL-C subgroup. Those with LDL-P > LDL-C had significantly greater body mass index, waist circumference, homeostatic model of insulin resistance, triglycerides, systolic and diastolic blood pressure, and reflected a greater Hispanic ethnic composition but fewer of black race than both the concordant (LDL-P ≅ LDL-C) and opposite discordant (LDL-P < LDL-C) subgroups. Conclusions: There is as much lipoprotein cholesterol compositional heterogeneity in sixth graders as has been described in adults and a discordant atherogenic phenotype of LDL-P > LDL-C, common in obesity, is often missed when only LDL-C is considered. Conversely, many children with moderate-risk cholesterol measures (75th to 99th percentile) have a lower LDL-P burden. [Copyright &y& Elsevier]

This review discusses the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults and compares it with the 2014 National Lipid Association (NLA) Recommendations for Patient-Centered Management of Dyslipidemia. The review discusses some of the distinctions between the guidelines, including how to determine a patient's atherosclerotic cardiovascular disease risk, the role of lipoprotein treatment targets, the importance of moderate- and high-intensity statin therapy, and the use of nonstatin therapy in light of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: We previously reported that serum PCSK9 levels are higher in postmenopausal women than in premenopausal women in a Han Chinese population. Whether this difference is related to estrogen has not been well-characterized. This study aims to examine if the alteration in estrogen level is responsible for the changes of serum PCSK9 concentration., Materials/methods: A sandwich ELISA assay was used to measure serum PCSK9 levels in 727 healthy women aged from 26 to 85 years old. Anthropometric and biochemical examination of parameters such as estrogen and serum lipids was also performed for these individuals. Next, we measured serum PCSK9 and estrogen levels of 30 healthy fertile women (24-26 years old) in their menstrual cycles and analyzed the correlation between serum PCSK9 level and estrogen concentration. Moreover, cell culture studies were carried out to examine if estrogen at physiological and non-physiological concentrations regulates hepatocyte PCSK9 expression., Results: Serum PCSK9 concentrations were significantly increased with aging. Aged group had higher serum PCSK9 levels than the middle aged group and the young group (60.29±28.47 vs 71.38±34.22 vs 83.81±33.50 ng/ml). Serum PCSK9 levels were positively correlated with age, BMI, serum total cholesterol and LDL-cholesterol (P<0.01), but not correlated with estrogen levels. There was no significantly difference of PCSK9 levels between the lower and the upper estradiol (E2) tertiles in the 727 women. There was either no significant difference in PCSK9 levels during the menstrual, ovulatory, luteal phases in the 30 healthy fertile women. Cell culture studies showed that 17β-estradiol at physiological concentrations did not significantly alter PCSK9 expression in human hepatocytes., Conclusion: The serum PCSK9 levels were higher in postmenopausal women than those in pre-menopausal women. However, the difference in serum PCSK9 levels between postmenopausal and premenopausal woman appeared to be independent of estrogen status, and estrogen at physiological concentrations does not affect human hepatocyte PCSK9 expression., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Coronary heart disease (CHD) affects 17 million people in the United States and accounts for over a million hospital stays each year. Technological advances, especially in genetics and genomics, have changed our understanding of the risk factors for developing CHD. The purpose of this article is to review low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and risk of CHD. The article focuses on five topics: (1) a description of lipoprotein classes, normal lipoprotein metabolism, and the biological mechanism of atherosclerosis; (2) a review of selected epidemiologic and clinical trial studies examining the associations between elevated LDL-C and apo B with CHD; (3) a brief review of the familial forms of hyperlipidemia; (4) a description of variants in genes that have been associated with higher LDL-C levels in candidate gene studies and genome-wide association studies (GWAS); and (5) nursing implications, including a discussion on how genetic tests are evaluated and the current clinical utility and validity of genetic tests for CHD.