Speciated High-Density Lipoprotein Biogenesis and Functionality.

Plasma high-density lipoprotein cholesterol (HDL-C) concentration is a negative risk factor for atherosclerotic cardiovascular disease (CVD). Despite this, most attempts to raise plasma HDL-C concentrations in a cardioprotective way have failed. Recently, hypotheses about the atheroprotective effects of HDL have shifted away from quantity to quality, mostly HDL function in reverse cholesterol transport. Plasma HDL from CVD patients is a poorer acceptor of cellular cholesterol than plasma from healthy controls, independent of plasma HDL-C concentrations. The function of HDL is likely determined by two other factors, stability and composition. The kinetic instability of HDL, which varies according to subclass, is a likely determinant of its reactivity in response to many HDL-modifying activities. HDL composition is also heterogeneous and variable; all HDL particles contain apo AI but only about two-thirds contain apo AII. This occurs despite the fact that apo AI and apo AII are hepatically secreted on separate HDL that later fuse in plasma. HDL also contains traces of other proteins, some of which have not yet been associated with HDL function. One minor HDL species are those that are secreted with intact signal peptides, which enhances their binding to HDL; these HDL have special properties that are independent of cholesterol transport. Here, we review and provide a perspective about what is currently known about speciated HDL biogenesis in the context of health and disease.

Merits and potential downsides of the 2013 ACC/AHA cholesterol management guidelines.

New guidelines from the American College of Cardiology and the American Heart Association on cholesterol management introduced substantial changes from the previous Adult Treatment Panel III guidelines and generated an immediate storm of controversy upon their release in November 2013. Four categories of individuals that can benefit from statin therapy, including three high-risk groups, have been identified. The fourth category of primary prevention has proven to be the most contentious, with criticism centering on the algorithm used to estimate ten-year risk for atherosclerotic cardiovascular disease and the optimal threshold for statin therapy. Although the risk assessment algorithm can be further refined, it represents an improvement from the previous calculator since it better captures risk in women and African Americans. However, the elimination of lipid targets in the new guidelines discounts a wealth of clinical trial and epidemiological evidence indicating that, with regards to low-density lipoprotein cholesterol, "lower is better." Recommendations regarding the use of nonstatin drugs, while appropriate, could potentially be revised in the future. In general, the new guidelines stress the necessity of addressing the multiple factors that contribute to cardiovascular risk, and they provide a valuable opportunity for physicians to address the importance of lifestyle modifications to lower a patient's overall risk.

The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials.

OBJECTIVES: To investigate whether statins reduce all cause mortality and major coronary and cerebrovascular events in people without established cardiovascular disease but with cardiovascular risk factors, and whether these effects are similar in men and women, in young and older (>65 years) people, and in people with diabetes mellitus. DESIGN: Meta-analysis of randomised trials. DATA SOURCES: Cochrane controlled trials register, Embase, and Medline. Data abstraction Two independent investigators identified studies on the clinical effects of statins compared with a placebo or control group and with follow-up of at least one year, at least 80% or more participants without established cardiovascular disease, and outcome data on mortality and major cardiovascular disease events. Heterogeneity was assessed using the Q and I(2) statistics. Publication bias was assessed by visual examination of funnel plots and the Egger regression test. RESULTS: 10 trials enrolled a total of 70 388 people, of whom 23 681 (34%) were women and 16 078 (23%) had diabetes mellitus. Mean follow-up was 4.1 years. Treatment with statins significantly reduced the risk of all cause mortality (odds ratio 0.88, 95% confidence interval 0.81 to 0.96), major coronary events (0.70, 0.61 to 0.81), and major cerebrovascular events (0.81, 0.71 to 0.93). No evidence of an increased risk of cancer was observed. There was no significant heterogeneity of the treatment effect in clinical subgroups. CONCLUSION: In patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events.

Activation of peroxisome proliferator-activated receptor-alpha in mice induces expression of the hepatic low-density lipoprotein receptor.

BACKGROUND AND PURPOSE: Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolaemia in humans and deletion of the LDLR induces lesion development in mice fed a high-fat diet. LDLR expression is predominantly regulated by sterol regulatory element-binding protein 2 (SREBP2). Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) ligand, belongs to a drug class used to treat dyslipidaemic patients. We have investigated the effects of fenofibrate on hepatic LDLR expression. EXPERIMENTAL APPROACH: The effects of fenofibrate on hepatic LDLR expression (mRNA and protein) and function were evaluated by both in vitro (with AML12 cells) and in vivo experiments in mice. KEY RESULTS: Fenofibrate increased LDLR expression and LDL binding in a mouse hepatoma cell line, AML12 cells. Fenofibrate restored sterol-inhibited hepatocyte LDLR expression. Mechanistic studies demonstrated that induction of LDLR expression by fenofibrate was dependent on PPARalpha and sterol regulatory elements (SRE). Specifically, fenofibrate induced LDLR expression by increasing maturation of SREBP2 and phosphorylation of protein kinase B (Akt) but had no effect on SREBP cleavage-activating protein. In vivo, a high-fat diet suppressed LDLR expression in mouse liver while elevating total and LDL cholesterol levels in plasma. However, fenofibrate restored LDLR expression inhibited by high-fat diets in the liver and reduced LDL cholesterol levels in plasma. CONCLUSIONS AND IMPLICATIONS: Our data suggest that fenofibrate increased hepatic LDLR expression in mice by a mechanism involving Akt phosphorylation and LDLR gene transcription mediated by SREBP2.

A trilogy of primary prevention statin trials. Panel discussion.

Presented is a report of a panel discussion held as part of the ISA 2006 Sankyo Forum titled "A Trilogy of Primary Prevention Statin Trials--The Impact of These Landmark Studies on Clinical Practice," Rome, Italy, June 2006. The themes of the panel discussion were the design features of three trials, WOSCOPS, AFCAPS/TexCAPS, and Japan's MEGA Study; comparison of their primary endpoints; and the implications of their results. Among the topics discussed by the panel of experts from Japan, USA, and UK were observations on the benefits associated with pravastatin at low dose as demonstrated in the MEGA Study as well as that study's implications for women, who represented the majority of subjects. Several suggestions were put forth to explain how the low dose used in MEGA elicited similar LDL-C reductions to those observed in WOSCOPS and AFCAPS/TexCAPS at higher doses including the body size hypothesis, genetic variation, and statin-diet interaction. It was felt that in Japan, the current guidelines are adequate; there seemed no merit in radically reducing LDL-C levels since in the Japanese population the risk is generally low. Japanese physicians tend to use small doses of statin and believe that these are effective in lowering cholesterol sufficiently with few side effects and encourage good compliance.

Establishing the benefit of statins in low-to-moderate--risk primary prevention: the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

AFCAPS/TexCAPS was the first prevention trial of a statin conducted in a low-to-moderate-risk cohort that included men (> or =45 years) and women (> or =55 years) with no evidence of atherosclerotic cardiovascular disease. At study entry, LDL-C had to be 130-190 mg/dL and HDL-C < or =45 mg/dL for men and < or =47 mg/dL for women. Participants were randomized to either lovastatin 20-40 mg/day (n=3304) or placebo (n=3301) for a mean follow-up period of 5.2 years. At 1 year, in the lovastatin group TC, LDL-C, and TG were reduced by 18.4%, 25.0%, and 15%, respectively. HDL-C increased by 6.0%. At 5 years, there was a 37% decrease in the relative risk for having a first acute coronary event in the lovastatin versus placebo group. Women showed similar relative risk reduction as men. Older individuals benefited as much as younger ones from lovastatin. Subjects with > or =2 risk factors benefited more from statin than those with <2 risk factors. At baseline, HDL-C but not TC or LDL-C was determined a significant predictor of risk. On treatment, ApoB and ApoA1 were the best predictors. Based on AFCAPS/TexCAPS, a simple heuristic could be that individuals with "age plus one other risk factor" may benefit from statin therapy in primary prevention.

Anti-adipogenic action of pitavastatin occurs through the coordinate regulation of PPARgamma and Pref-1 expression.

BACKGROUND AND PURPOSE: Adipocyte differentiation in vitro is coordinately activated by two transcription factors, peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT enhancer binding protein alpha (C/EBPalpha), but it is inhibited by preadipocyte factor-1 (pref-1). Statins, inhibitors of HMG-CoA reductase and de novo cholesterol synthesis, can have pleiotropic effects which influence adipocyte phenotype by ill-defined mechanisms. We investigated the effects of pitavastatin (NK-104) on adipocyte differentiation and the transcriptional pathways involved. EXPERIMENTAL APPROACH: The effects of pitavastatin on adipocyte differentiation were evaluated by the formation of oil droplets, content of cellular triglyceride and expression of adipocyte-specific genes. Regulatory mechanisms were assessed by analysis of PPARgamma, C/EBPalpha and pref-1 expression. KEY RESULTS: Pitavastatin significantly inhibited adipocyte differentiation of 3T3-L1 preadipocytes in response to adipogenic inducers. Evidence for inhibition included fewer Oil Red O positive droplets, less cellular triglyceride and decreased expression of adipocyte-specific genes, including fatty acid binding protein (aP2), CD36, adipsin and glucose transporter 4 (GLUT4). The inhibitory effects of pitavastatin on adipocyte differentiation of 3T3-L1 preadipocytes were time and concentration dependent. Pitavastatin significantly blocked induction of PPARgamma expression, but not C/EBPalpha expression or DNA binding activity of PPARgamma. Also, pitavastatin induced pref-1 expression in preadipocytes and maintained expression of pref-1 at high levels in differentiated cells. CONCLUSIONS AND IMPLICATIONS: Our data suggest that pitavastatin inhibits adipocyte differentiation by blocking PPARgamma expression and activating pref-1 expression. These studies may have implications in the regulation of adipogenesis in response to statins.

High-density lipoprotein cholesterol: an updated view.

New insights into low high-density lipoprotein cholesterol identify promising new directions for coronary heart disease prevention. The ATP-binding-cassette A1 gene has been identified as an important defect in genetic disorders of this lipid fraction. Recent studies indicate a benefit in treating patients with low levels of high-density lipoprotein cholesterol and suggest new clinical recommendations.

Emerging perspectives on lipid management: international approaches and global challenges.

The rapid growth in the understanding of the relation between cholesterol and coronary heart disease has introduced new challenges to the contemporary management of lipid disorders. The publication of the trials of the 3-hydroxy-3-methylglutaryl coenzyme-A inhibitors (statins) has invigorated support for the lipid hypothesis, and many advances have been made in understanding the mechanisms underlying atherosclerosis and the potential benefits of the statins. Several international groups have issued guidelines about desirable and undesirable lipid values to help clinical decision making. Despite the availability of such principles, there are many challenges to optimal management of lipid disorders.

How do we achieve optimal cardiovascular risk reduction?

Optimizing coronary heart disease (CHD) risk reduction requires the application of clinical evidence to patient care, as well as the refinement of risk assessment. Clinical evidence indicates that most patients are not treated to optimal low-density lipoprotein (LDL) cholesterol goals. Despite the efficacy of statin therapy in reducing the incidence of CHD, many treated patients still experience CHD events. Targeting other lipid factors such as high-density lipoprotein cholesterol and triglycerides may augment the risk reduction achieved by lowering LDL cholesterol. Refined global risk assessment can lead to more accurate determinations of absolute risk and to the identification both of high-risk patients needing aggressive intervention and intermediate-risk patients who appear to be at low risk. Previous global risk assessment measures failed to identify a substantial proportion of primary prevention patients who would benefit from therapy. However, revised guidelines issued by the National Cholesterol Education Program introduce new criteria for more precise risk assessment and advocate use of the Framingham scoring system to calculate absolute risk. Although intensified treatment is recommended for high-risk patients, cost considerations may limit drug therapy for some lower-risk individuals.

Ongoing clinical trials of statins.

Lipid-lowering treatment with statins is effective for primary and secondary prevention of coronary artery disease in patients with either hypercholesterolemia or average cholesterol levels. Several clinical trials in progress will investigate the use of statins in entirely elderly or diabetic cohorts, and larger trials will continue to include significant numbers of these patients, as well as greater numbers of women. Additional clinical endpoint trials are assessing the potential benefits of lowering lipid levels to below currently recommended goals and of aggressive early statin treatment to prevent ischemic events in patients with stable coronary disease or acute coronary syndromes. These trials are expected to yield important data on the relation of lipid reduction to the prevention of coronary artery disease and on the potential for extending the use of statins.

Pleiotropic effects of statins: do they matter?

Treatment with the 3-hydroxy-3-methylglutaryl coenyzme A reductase inhibitors (or statins) reduces the risk for cardiovascular events across a broad spectrum of patient profiles, as evidenced by both primary prevention and secondary prevention trials. Improved survival by way of reduced deaths from coronary heart disease was also reported with these agents, which are primarily indicated for substantial reduction in LDL-cholesterol levels. However, the statins are extremely complex drugs and exhibit a wide variety of vascular effects that may or may not be dependent on their lipid-modifying properties. These so-called pleiotropic effects include alterations of endothelial function, inflammation, coagulation, and plaque stability. The relative contribution of the nonlipid effects of statin therapy to the well-documented clinical benefits is currently under intense investigation.

Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.

BACKGROUND: Elevated levels of C-reactive protein, even in the absence of hyperlipidemia, are associated with an increased risk of coronary events. Statin therapy reduces the level of C-reactive protein independently of its effect on lipid levels. We hypothesized that statins might prevent coronary events in persons with elevated C-reactive protein levels who did not have overt hyperlipidemia. METHODS: The level of C-reactive protein was measured at base line and after one year in 5742 participants in a five-year randomized trial of lovastatin for the primary prevention of acute coronary events. RESULTS: The rates of coronary events increased significantly with increases in the base-line levels of C-reactive protein. Lovastatin therapy reduced the C-reactive protein level by 14.8 percent (P<0.001), an effect not explained by lovastatin-induced changes in the lipid profile. As expected, lovastatin was effective in preventing coronary events in participants whose base-line ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol was higher than the median ratio, regardless of the level of C-reactive protein (number needed to treat for five years to prevent 1 event, 47; P=0.005). However, lovastatin was also effective among those with a ratio of total to HDL cholesterol that was lower than the median and a C-reactive protein level higher than the median (number needed to treat, 43; P=0.02). In contrast, lovastatin was ineffective among participants with a ratio of total to HDL cholesterol and a C-reactive protein level that were both lower than the median (number needed to treat, 983; P=0.80). CONCLUSIONS: Statin therapy may be effective in the primary prevention of coronary events among subjects with relatively low lipid levels but with elevated levels of C-reactive protein.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS): additional perspectives on tolerability of long-term treatment with lovastatin.

This study presents the long-term safety data from AFCAPS/TexCAPS, the first primary prevention trial to demonstrate that men and women with average levels of low-density lipoprotein cholesterol (LDL-C) and below average levels of high-density lipoprotein cholesterol (HDL-C) can significantly benefit from long-term treatment to lower LDL-C; lovastatin 20 to 40 mg/day reduced the risk of a first acute major coronary event (fatal or nonfatal myocardial infarction, unstable angina, or sudden death) by 37% (p = 0.00008). This double-blind randomized, placebo-controlled trial, in 6,605 generally healthy middle-aged and older men and women, had prespecified end point and cancer analyses. All analyses were intention-to-treat. Safety monitoring included history, physical examination, and laboratory studies (including hepatic transaminases and creatine phosphokinase [CPK]). All participants, even those who discontinued treatment, were contacted annually for vital status, cardiovascular events, and cancer history. After an average of 5.2 years of follow-up, there were 157 deaths (80 receiving lovastatin and 77 receiving placebo; relative risk [RR] 1.04; 95% confidence interval [CI] 0.76 to 1.42; p = 0.82); of which 115 were noncardiovascular (RR 1.21; CI 0.84 to 1.74; p = 0.31), and of these, 82 were due to cancer (RR 1.41; CI 0.91 to 2.19; p = 0.13). There were no significant differences between treatment groups in overall cancer rates, discontinuations for noncardiovascular adverse experiences, or clinically important elevations of hepatic transaminases or CPK. Among those who used cytochrome P450 isoform (CYP3A4) inhibitors, there were no treatment group differences in the frequency of clinically important muscle-related adverse events. Treatment with lovastatin 20 to 40 mg daily for primary prevention of coronary heart disease was well tolerated and reduced the risk of first acute coronary events without increasing the risk of either noncardiovascular mortality or cancer.

Novel polymorphisms in promoter region of atp binding cassette transporter gene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy.

Identification of mutations in the ATP binding cassette transporter (ABCA1) gene in patients with Tangier disease, who exhibit reduced HDL cholesterol (HDL-C) and apolipoprotein A1 (apoA1) levels and premature coronary atherosclerosis, has led to the hypothesis that common polymorphisms in the ABCA1 gene could determine HDL-C and apoA1 levels and the risk of coronary atherosclerosis in the general population. We sequenced a 660-bp 5' fragment of the ABCA1 gene in 24 subjects and identified 3 novel polymorphisms: -477C/T, -419A/C, and -320G/C. We developed assays, genotyped 372 participants in the prospective Lipoprotein Coronary Atherosclerosis Study (LCAS), and determined the association of the variants with fasting plasma lipids and indices of quantitative coronary angiograms obtained at baseline and 2.5 years after randomization to fluvastatin or placebo. Distribution of -477C/T and -320G/C genotypes were 127 CC, 171 CT, and 74 TT and 130 GG, 168 GC, and 75 CC, respectively, and were in complete linkage disequilibrium (P<0.0001). Data for -477C/T are presented. The -419A/C variant was uncommon (present in 1 of 63 subjects). Heterozygous subjects had a modest reduction in HDL-C (P=0.09) and apoA1 (P=0.05) levels and a lesser response of apoA1 to treatment with fluvastatin (P=0.04). The mean number of coronary lesions causing 30% to 75% diameter stenosis was greater in subjects with the TT genotype (3.1+/-2.1) or CT genotype (2.9+/-1.9) than in subjects with the CC genotype (2.2+/-1.8) (P=0.002). Similarly, compared with subjects with the CC genotype, greater numbers of subjects with the TT or CT genotype had >/=1 coronary lesion (P=0.001). No association between the genotypes and progression of coronary atherosclerosis or clinical events was detected. We conclude that ABCA1 genotypes are potential risk factors for coronary atherosclerosis in the general population.

A prospective study of paraoxonase gene Q/R192 polymorphism and severity, progression and regression of coronary atherosclerosis, plasma lipid levels, clinical events and response to fluvastatin.

Human serum paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme that is responsible for the protective effect of HDL against oxidation of low-density lipoprotein (LDL). PON1 has a Glu to Arg polymorphism at codon 192 (CGA-->CAA) which is designated R/Q192. The R/Q192 polymorphism has been associated with coronary artery disease (CAD) in several, but not all, case-control studies. We prospectively studied the association of the Q/R192 genotypes with the severity, progression and regression of CAD, plasma lipid levels, clinical events and response to treatment with fluvastatin in a well-characterized cohort. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping with AlwI enzyme in 356 subjects in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. A total of 177 (50%), 142 (40%) and 37 (10%) subjects had Q/Q, Q/R and R/R genotypes, respectively. Baseline and final plasma levels of HDL, LDL, triglyceride and other lipoproteins, lesion-specific minimum lumen diameters (MLD), mean MLD, number of coronary lesions and total occlusions at baseline and follow-up and clinical event rates were not significantly different among the genotypes. There was no genotype-treatment interaction with respect to plasma lipid levels and angiographic indices of CAD. The Q/R192 variants of PON1 are not associated with severity, progression or regression of coronary atherosclerosis, plasma lipid levels, clinical events, or response to treatment with fluvastatin. Thus, the Q/R192 polymorphism is not a major risk factor in susceptibility to CAD in the LCAS population.

Statin therapy: where are we? Where do we go next?

Statin therapy reduces coronary artery disease morbidity and mortality in primary and secondary prevention trials including patients with elevated and average cholesterol levels. The association between reduction of total or low-density lipoprotein cholesterol and preventive benefit is well established. However, additional risk factors for coronary artery disease need to be incorporated into risk assessment to provide an accurate measure of global risk for use in lifestyle intervention and drug therapy guidelines. Assessment of outcomes in the Air Force/Texas Coronary Atherosclerosis Prevention Study primary prevention trial, which involved patients with average cholesterol levels and reduced high-density lipoprotein cholesterol (HDL-C), suggests the importance of on-treatment values of apolipoproteins B and A-I in predicting first major events in such a population. Other data, including trials of fibrate therapy showing reduction in coronary artery disease events, support the importance of triglycerides and HDL-C in coronary artery disease risk. Challenges for future treatment guidelines include incorporation of emerging and novel risk factors into risk assessment, refinement of global risk measurement, and simplification for application to clinical practice.