A low level of high-density lipoprotein cholesterol (HDL-C) is an important risk factor for cardiovascular disease. Epidemiological and clinical studies provide evidence that HDL-C levels are linked to rates of coronary events. The cardioprotective effects of HDL-C have been attributed to its role in reverse cholesterol transport, its effects on endothelial cells, and its antioxidant activity. Although some clinical trials suggest a benefit of raising HDL-C to reduce risk, further studies are needed, and HDL-C is still not considered a primary target of therapy in the National Cholesterol Education Program guidelines. However, HDL-C should be considered as part of the patient's overall profile of established risk factors in determining treatment strategies.

ATP Binding Cassette Transporter 1↗

PubMed2004

Inflammation in atherosclerosis and implications for therapy.

Atherosclerosis is now understood to be a disease characterized by inflammation that results in a host of complications, including ischemia, acute coronary syndromes (unstable angina pectoris and myocardial infarction), and stroke. Inflammation may be caused by a response to oxidized low-density lipoproteins, chronic infection, or other factors; and markers of this process, such as C-reactive protein, may be useful to predict an increased risk of coronary heart disease. Thus, we believe that inflammatory processes may be potential targets of therapy in preventing or treating atherosclerosis and its complications.

Acute-Phase Reaction↗

PubMed2004

Past, present, and future standards for management of dyslipidemia.

Evolution of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines for lipid lowering reflects a movement toward global risk assessment, including improved identification of risk in individuals without established coronary heart disease (CHD), and toward more aggressive lipid-lowering targets to reduce CHD risk. The current guidelines, for example, identify a segment of the population without established CHD as being at high risk on the basis of criteria that indicate CHD risk equivalency, recommend a low-density lipoprotein cholesterol (LDL-C) plasma level <100 mg/dL as optimal in all individuals, and establish the metabolic syndrome as a secondary target for therapeutic intervention. Many questions remain for future guidelines to address: To what extent should plasma levels of LDL-C be lowered by therapy to afford optimal risk reduction? Can risk assessment be improved, e.g., by using novel risk measures (such as high-sensitivity C-reactive protein) to indicate patients at higher risk who may benefit from more aggressive interventions? Should the metabolic syndrome be considered a high-risk state warranting aggressive intervention irrespective of risk categorization using current scoring methods? Guidelines for lipid management represent a synthesis of constantly emerging and evolving data: ongoing efforts to improve understanding of the relation between dyslipidemia and cardiovascular disease, to increase knowledge of and ability to measure other CHD risk factors, and to improve therapeutic practices and options will be reflected in future guidelines.

Cholesterol, LDL↗

PubMed2004

Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update.

Clinical data show that a 1% increase in serum concentrations of high-density lipoprotein cholesterol (HDL-C) can decrease cardiovascular risk by 2% to 3%. Therefore, mechanisms affecting the level and functionality of high-density lipoprotein (HDL) and its constituents are being investigated as targets for the rational development of drugs to prevent or treat cardiovascular disease. High-density lipoprotein-related research may also increase our understanding of the link between atherosclerosis and metabolic disorders. This report and update of the HDL Working Group discusses HDL metabolism and reverse cholesterol transport, impaired HDL as a marker and a cause of proatherogenic states, and experimental and current approaches to HDL-related therapy.

Arteriosclerosis↗

PubMed2004

Pitavastatin downregulates expression of the macrophage type B scavenger receptor, CD36.

BACKGROUND: Pitavastatin (NK-104) is a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol biosynthesis. In clinical trials, pitavastatin has been shown to significantly decrease serum LDL cholesterol and triglyceride levels and increase HDL cholesterol. Scavenger receptor-mediated accumulation of oxidized LDL (OxLDL)-derived cholesteryl ester is considered to be a critical step in the development of atherosclerotic foam cell formation. We studied the effect of pitavastatin on CD36 (a class B scavenger receptor) expression by murine macrophages. METHODS AND RESULTS: Treatment of J774 cells and murine peritoneal macrophages with pitavastatin decreased CD36 mRNA expression in a dose-dependent manner. Decreased CD36 mRNA was associated with decreased CD36 cell surface protein expression in human THP-1 cells and human monocyte-derived macrophages. Pitavastatin also reduced the increase in CD36 mRNA, cell surface protein, and binding/uptake of OxLDL induced by peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands and/or OxLDL. Pitavastatin did not alter the half-life of CD36 mRNA, which suggests pitavastatin downregulates CD36 expression by reducing CD36 transcription. In addition, pitavastatin significantly decreased PPARgamma mRNA and protein expression. Finally, pitavastatin increased p44/42 mitogen-activated protein kinase activity and PPARgamma phosphorylation and increased the ratio of phosphorylated PPARgamma to nonphosphorylated PPARgamma. CONCLUSIONS: The present data demonstrate that pitavastatin prevents OxLDL uptake by macrophages through PPARgamma-dependent inhibition of CD36 expression and suggest that pitavastatin could modulate CD36-mediated atherosclerotic foam cell formation.

Animals↗

PubMed2004

The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

The metabolic syndrome, which is a set of lipid and nonlipid risk factors of metabolic origin linked with insulin resistance, is believed to be associated with an elevated risk for cardiovascular disease, but few have studied this association in prospective long-term cardiovascular outcomes trials. Placebo data from the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) were used post hoc to estimate the long-term relative risk of major coronary events (MCEs) associated with the metabolic syndrome, after excluding diabetes mellitus. In 4S and AFCAPS/TexCAPS, respectively, placebo-treated patients with the metabolic syndrome were 1.5 (95% confidence interval 1.2 to 1.8) and 1.4 (95% confidence interval 1.04 to 1.9) times more likely to have MCEs than those without it. Of the components of the metabolic syndrome, low high-density lipoprotein levels were associated with elevated risk of MCEs in both studies, whereas high triglycerides in 4S and elevated blood pressure and obesity in AFCAPS/TexCAPS were associated with significantly increased relative risk. Patients with the metabolic syndrome showed increased risk of MCEs irrespective of their Framingham-calculated 10-year risk score category (>20% vs </=20%). These data demonstrate that the metabolic syndrome is associated with increased risk of MCEs in both hypercholesterolemic patients with coronary heart disease in 4S and in those with low high-density lipoprotein cholesterol but without coronary heart disease in AFCAPS/TexCAPS. It appears that the metabolic syndrome is associated with risk that is not entirely accounted for by traditional risk scoring paradigms.

Anticholesteremic Agents↗

PubMed2004

Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study.

Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and Coronary Atherosclerosis Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of coronary atherosclerosis and its response to therapy.

Algorithms↗

PubMed2003

Pitavastatin alters the expression of thrombotic and fibrinolytic proteins in human vascular cells.

In addition to lowering blood lipids, clinical benefits of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A; EC 1.1.1.34) reductase inhibitors may derive from altered vascular function favoring fibrinolysis over thrombosis. We examined effects of pitavastatin (NK-104), a relatively novel and long acting statin, on expression of tissue factor (TF) in human monocytes (U-937), plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator (t-PA) in human aortic smooth muscle cells (SMC) and human umbilical vein endothelial cells (HUVEC). In monocytes, pitavastatin reduced expression of TF protein induced by lipopolysaccharide (LPS) and oxidized low-density lipoprotein (OxLDL). Similarly, pitavastatin also reduced expression of TF mRNA induced by LPS. Pitavastatin reduced PAI-1 antigen released from HUVEC under basal, OxLDL-, or tumor necrosis factor-alpha (TNF-alpha)-stimulated conditions. Reductions of PAI-1 mRNA expression correlated with decreased PAI-1 antigen secretion and PAI-1 activity as assessed by fibrin-agarose zymography. In addition, pitavastatin decreased PAI-1 antigen released from OxLDL-treated and untreated SMC. Conversely, pitavastatin enhanced t-PA mRNA expression and t-PA antigen secretion in untreated OxLDL-, and TNF-alpha-treated HUVEC and untreated SMC. Finally, pitavastatin increased t-PA activity as assessed by fibrin-agarose zymography. Our findings demonstrate that pitavastatin may alter arterial homeostasis favoring fibrinolysis over thrombosis, thereby reducing risk for thrombi at sites of unstable plaques.

Animals↗

PubMed2003

Adipogenic differentiating agents regulate expression of fatty acid binding protein and CD36 in the J744 macrophage cell line.

Adipocyte fatty acid binding protein (aP2) is a key mediator of intracellular transport and metabolism of fatty acids. Its expression during adipocyte differentiation is regulated through the actions of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha). Macrophages also express aP2, and the lack of macrophage aP2 significantly reduces atherosclerotic lesion size in hypercholesterolemic mice. We investigated the regulation of expression of macrophage aP2 and CD36, a fatty acid membrane binding protein and scavenger receptor, in response to the adipogenic agents isobutylmethylxanthine (IBMX), insulin, and dexamethasone, a combination of agents shown to induce fibroblast-to-adipocyte differentiation. Treatment of J774 macrophages with adipogenic agents significantly induced aP2 mRNA expression, while CD36 expression was inhibited. Dexamethasone was essential and sufficient to induce aP2 expression, and insulin had a synergistic effect. However, IBMX antagonized induced-aP2 expression. aP2 protein expression and [14C]oleic acid uptake by macrophages were also increased by dexamethasone. Unlike what occurs in adipocytes, adipogenic agents had mixed effects on the expression of PPARgamma and C/EBPalpha in macrophages. Our data demonstrate differences in the regulation of aP2 in adipocytes and macrophages and show that macrophage aP2 expression by adipogenic agents is independent of the PPARgamma and/or C/EBPalpha signaling pathway.

1-Methyl-3-isobutylxanthine↗

PubMed2003

The Heart Protection Study: expanding the boundaries for high-risk coronary disease prevention.

Clinical trial evidence strongly favors aggressive risk factor modification in the prevention of coronary artery disease (CAD). The latest landmark trial of therapy using a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) is the Heart Protection Study (HPS) of simvastatin versus placebo in a cohort of patients at high risk for CAD. The HPS reported a number of highly significant reductions in the risk for major vascular events with treatment. It also provides new insights into the effects of statin therapy in patient subgroups, such as the elderly, women, and those with noncoronary vascular disease. These data are likely to have an important influence on the future of cardiovascular disease prevention.

Clinical Trials as Topic↗

PubMed2003

Antioxidants, statins, and atherosclerosis.

Research into the oxidation of lipoproteins has yielded many new insights into the pathogenesis of atherosclerosis. However, despite lipoprotein oxidation's biologically plausible role in atherogenesis, several studies have reported inconsistent effects of antioxidants on clinical coronary end points, in sharp contrast with the studies of lipid modification with the 3-hydroxy-3-methylglutaryl coenzyme A inhibitors, or statins. There appears to be little support for the use of antioxidants in coronary prevention. However, the picture remains incomplete. What are the limitations of available antioxidant studies and the agents used? Until the picture can be clarified, lipid modification with strategies proved to reduce the risk for coronary events, such as statins or dietary changes in the style of the Mediterranean diet, should be better implemented in clinical practice.

Animals↗

PubMed2003

Safety and statin therapy: reconsidering the risks and benefits.

Explore the source record for details and available documents.

Anticholesteremic Agents↗

PubMed2003

Treating hypercholesterolemia: looking forward.

Despite important advances in the management of hypercholesterolemia in recent decades, many patients with lipid disorders remain unidentified or undertreated and so continue to have unfavorable levels of low-density lipoprotein (LDL) cholesterol and an increased risk for coronary events. The statins--which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis--have proved to be the most powerful pharmacologic agents for lowering serum lipids, and newer statins offer even greater efficacy than the agents introduced 10 to 15 years ago. Studies have shown that rosuvastatin, in late-stage development, is a very potent agent for the treatment of primary hypercholesterolemia, and that relatively low doses decrease LDL cholesterol levels to a greater extent than do similar doses of pravastatin, simvastatin, or atorvastatin as evaluated in separate clinical trials. Pitavastatin, in phase II trials, also has promise as a more potent drug than currently available statins. Because neither of these drugs has been approved for use in the United States, clinical trial results should be considered preliminary. In the future, agents that combine the actions of statins and nicotinic acid may achieve still greater LDL cholesterol reductions. Drugs that lower lipids via mechanisms other than inhibition of HMG-CoA reductase also offer promise. The newest addition to the roster of lipid-regulating agents is ezetimibe, a cholesterol absorption inhibitor that has been approved for use either alone or in combination with a statin. Agents in development include bile acid transport inhibitors and inhibitors of acyl CoA:cholesterol acyltransferase. More research will be needed to determine the full clinical potential of such approaches to the management of hypercholesterolemia.

Anticholesteremic Agents↗