The mechanism and mitigation of niacin-induced flushing.

AIMS: To summarise the metabolic responses to niacin that can lead to flushing and to critically evaluate flushing mitigation research. METHODS AND RESULTS: This comprehensive review of the mechanism of action of niacin-induced flushing critically evaluates research regarding flushing mitigating formulations and agents. Niacin induces flushing through dermal Langerhans cells where the activation of G protein-coupled receptor 109A (GPR109A) increases arachidonic acid and prostaglandins, such as prostaglandin D(2) (PGD(2)) and prostaglandin E(2) (PGE(2)), subsequently activating prostaglandin D(2) receptor (DP(1)), prostaglandin E(2) receptor (EP(2)) and prostaglandin E receptor 4 (EP(4)) in capillaries and causing cutaneous vasodilatation. Controlling niacin absorption rates, inhibiting prostaglandin production, or blocking DP(1), EP(2) and EP(4) receptors can inhibit flushing. Niacin extended-release (NER) formulations have reduced flushing incidence, duration and severity relative to crystalline immediate-release niacin with similar lipid efficacy. Non-steroidal anti-inflammatory drugs (NSAIDs), notably aspirin given 30 min before NER at bedtime, further reduce flushing. An antagonist to the DP(1) receptor (laropiprant) combined with an ER niacin formulation can reduce flushing; however, significant residual flushing occurs with clinically-relevant dosages. CONCLUSIONS: Niacin is an attractive option for treating dyslipidemic patients, and tolerance to niacin-induced flushing develops rapidly. Healthcare professionals should particularly address flushing during niacin dose titration.

Niacin, but not gemfibrozil, selectively increases LP-AI, a cardioprotective subfraction of HDL, in patients with low HDL cholesterol.

Evidence indicates that the high density lipoprotein (HDL) subfraction containing apolipoprotein A-I without apolipoprotein AII (LP-AI) is more antiatherogenic than HDL particles containing apolipoprotein A-I and apolipoprotein A-II (LP-AI+AII). This study examined the effect of extended-release niacin (niacin-ER) and gemfibrozil on LP-AI and LP-AI+AII particles in patients with low levels of HDL cholesterol (HDL-C). Mechanisms by which these agents modulate HDL particles were investigated by in vitro studies using human hepatoblastoma (Hep G2) cells. A total of 139 patients with low HDL-C (

Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial.

CONTEXT: A low plasma level of high-density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD). A secondary prevention study, the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), demonstrated that CHD events were significantly reduced during a median follow-up of 5.1 years by treating patients with the fibric acid derivative gemfibrozil when the predominant lipid abnormality was low HDL-C. OBJECTIVE: To determine if the reduction in major CHD events with gemfibrozil in VA-HIT could be attributed to changes in major plasma lipid levels. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial conducted from September 1991 to August 1998. SETTING: The Department of Veterans Affairs Cooperative Studies Program, in which 20 VA medical centers were participating sites. PARTICIPANTS: A total of 2531 men with a history of CHD who had low HDL-C levels (mean, 32 mg/dL [0.83 mmol/L] ) and low low-density lipoprotein cholesterol (LDL-C) levels (mean, 111 mg/dL [2.88 mmol/L]). INTERVENTION: Participants were randomly assigned to receive gemfibrozil, 1200 mg/d (n = 1264), or matching placebo (n = 1267). MAIN OUTCOME MEASURE: Relation of lipid levels at baseline and averaged during the first 18 months of gemfibrozil treatment with the combined incidence of nonfatal myocardial infarction and CHD death. RESULTS: Concentrations of HDL-C were inversely related to CHD events. Multivariable Cox proportional hazards analysis showed that CHD events were reduced by 11% with gemfibrozil for every 5-mg/dL (0.13-mmol/L) increase in HDL-C (P =.02). Events were reduced even further with gemfibrozil beyond that explained by increases in HDL-C values, particularly in the second through fourth quintiles of HDL-C values during treatment. During gemfibrozil treatment, only the increase in HDL-C significantly predicted a lower risk of CHD events; by multivariable analysis, neither triglyceride nor LDL-C levels at baseline or during the trial predicted CHD events. CONCLUSIONS: Concentrations of HDL-C achieved with gemfibrozil treatment predicted a significant reduction in CHD events in patients with low HDL-C levels. However, the change in HDL-C levels only partially explained the beneficial effect of gemfibrozil.

The benefits of niacin in atherosclerosis.

Niacin favorably alters all major lipid subfractions at pharmacologic doses. Alone or in combination, it promotes regression of coronary artery disease, decreases coronary events, stroke, and total mortality. Major recent progress in niacin is in four areas. Firstly, recent data indicate that it increases high-density lipoprotein (HDL) and lowers triglycerides and low-density lipoprotein (LDL) by mechanisms different from statins, fibrates, and bile-sequestrants, giving rationale for combination therapy to achieve synergistic effects for complete lipid goal achievement. Secondly, new data on an extended-release preparation of niacin given once nightly indicates that it is as effective and has greater tolerability than immediate-release niacin. Thirdly, preliminary data with a single tablet formulation extended-release niacin and an HMG CoA reductase inhibitor (lovastatin) shows it to be safe and very effective, especially for raising HDL. Finally, emerging evidence indicates that niacin can be used effectively and safely in patients with type 2 diabetes mellitus, who often have low HDL levels.

Mechanism of action of niacin on lipoprotein metabolism.

It is generally accepted that the increased concentrations of apolipoprotein (apo) B containing very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), and decreased levels of apo AI containing high-density lipoproteins (HDL) are correlated to atherosclerotic cardiovascular disease. Current evidence indicates that the post-translational apo-B degradative processes regulate the hepatic assembly and secretion of VLDL and the subsequent generation of LDL particles. The availability of triglycerides (TG) for the addition to apo B during intracellular processing appears to play a central role in targeting apo B for either intracellular degradation or assembly and secretion as VLDL particles. Based on the availability of TG, the liver secretes either dense TG-poor VLDL2 or large TG-rich VLDL1 particles, and these particles serve as precursors for the formation of more buoyant or small, dense LDL particles by lipid transfer protein- and hepatic lipase-mediated processes. HDLs are a heterogenous class of lipoproteins, and apo AI (the major protein of HDL) participates in reverse cholesterol transport, a process by which excess cholesterol is eliminated. Recent studies indicate that HDL particles containing only apo A-I (LPA-I) are more effective in reverse cholesterol transport and more anti-atherogenic than HDL particles containing both apo A-I and apo A-II (LPA-I + A-II).

Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group.

OBJECTIVE: To provide a direct comparison of agents that raise plasma levels of high-density lipoprotein cholesterol (HDL-C) to help devise strategies for coronary risk reduction. METHODS: In a multicenter, randomized, double-blind trial, we compared the effects of extended-release niacin (Niaspan), at doses increased sequentially from 1000 to 2000 mg at bedtime, with those of gemfibrozil, 600 mg given twice daily, in raising low levels of HDL-C. Enrollment criteria included an HDL-C level of 1.03 mmol/L or less (< or =40 mg/dL), a low-density lipoprotein cholesterol level of 4.14 mmol/L or less (< or =160 mg/dL) or less than 3.36 mmol/L (<130 mg/dL) with atherosclerotic disease, and a triglyceride level of 4.52 mmol/L or less (< or =400 mg/dL). RESULTS: Among 173 patients, 72 (82%) of the 88 assigned to Niaspan treatment and 68 (80%) of the 85 assigned to gemfibrozil treatment completed the study. Niaspan, at 1500 and 2000 mg, vs gemfibrozil raised the HDL-C level more (21% and 26%, respectively, vs 13%), raised the apolipoprotein A-I level more (9% and 11% vs 4%), reduced the total cholesterol-HDL-C ratio more (-17% and -22% vs -12%), reduced the lipoprotein(a) level (-7% and -20% vs no change), and had no adverse effect on the low-density lipoprotein cholesterol level (2% and 0% change vs a 9% increase). Significance levels for comparisons between medications ranged from P<.001 to P<.02. Gemfibrozil reduced the triglyceride level more than Niaspan (P<.001 to P = .06, -40% for gemfibrozil vs -16% to -29% for Niaspan, 1000 to 2000 mg). Effects on plasma fibrinogen levels were significantly favorable for Niaspan compared with gemfibrozil (P<.02), as gemfibrozil increased the fibrinogen level (from 5% to 9%) and Niaspan tended to decrease the fibrinogen level (from -1% to -6%). CONCLUSIONS: In patients with a low baseline HDL-C level, Niaspan at its higher doses provided up to 2-fold greater HDL-C increases, decreases in lipoprotein(a), improvements in lipoprotein cholesterol ratios, and lower fibrinogen levels compared with gemfibrozil. Gemfibrozil gave a greater triglyceride reduction but also increased the low-density lipoprotein cholesterol level, which did not occur with Niaspan.

Albumin inhibits apolipoprotein AI and AII production in human hepatoblastoma cell line (Hep G2): additive effects of oleate-albumin complex.

Although the role of multiple humoral agents (such as plasma albumin, glucose, hormones etc.) are implicated in lipoprotein metabolism, the mechanism of action of these agents on various steps of the synthesis and secretion of lipoproteins and apolipoproteins (protein moieties of lipoproteins) are not completely understood. Specifically, the hepatocellular mechanisms of the effect of albumin and fatty acids on apolipoprotein (apo) AI and AII [major proteins of high density lipoproteins (HDL)] synthesis and secretion are not known. Using human hepatoblastoma cells (Hep G2) as an in vitro model system, this study examined the effect of albumin and fatty acids on the synthesis, secretion, and the steady-state mRNA expression of apo AI and AII. The data indicated that the incubation of Hep G2 cells with albumin, dose-dependently, inhibited apo AI and AII accumulation (secretion) in the media, de novo synthesis, and the steady-state mRNA expression. Albumin did not alter total protein synthesis; thus the effect of albumin appeared to be specific for the synthesis and secretion of apo AI and apo AII. Free fatty acids (FFA) are transported by albumin and diseases characterized by enhanced FFA mobilization (e.g. diabetes mellitus) are associated with low HDL levels. Studies were therefore performed to examine the effect of albumin-bound-oleic acid on apo AI and apo AII production. The results showed that the albumin-oleate complex further increased the inhibitory effects of albumin on apo AI and apo AII production. These data suggest how HDL metabolism may be affected at the hepatocellular level by alterations in plasma albumin concentrations and/or fatty acid mobilization in clinical situations characterized by altered HDL levels.

Dietitian intervention improves lipid values and saves medication costs in men with combined hyperlipidemia and a history of niacin noncompliance.

We asked if medical nutrition therapy (MNT) administered by registered dietitians could lead to beneficial clinical and financial outcomes in men with combined hyperlipidemia (hypercholesterolemia and hypertriglyceridemia). A retrospective chart review was conducted on 73 men with combined hyperlipidemia who were being considered for statin therapy because of a previous history of noncompliance with niacin therapy. Subjects participated in an 8-week dietitian intervention program as a qualifying requirement, before statin therapy. Patient records were reviewed to determine the beginning and ending serum lipid concentrations and the number and length of dietitian sessions. Complete information was available on 43 subjects, aged 60.7 +/- 10.1 years (mean +/- standard deviation). Total dietitian intervention time was 169 +/- 19 minutes in 2.7 +/- 0.6 sessions (range = 2 to 4 sessions) during 6.5 +/- 2.2 weeks of MNT (range = 4 to 8 weeks). MNT lowered levels of total cholesterol 11% (P < .001), low-density lipoprotein cholesterol 9% (P < .001), and triglycerides 22% (P < .0001) and body mass index 2% (P < .0001); MNT raised high-density lipoprotein cholesterol levels 4%. After dietitian intervention, only 15 of 30 eligible patients required antihyperlipidemic medications, which led to an annual cost savings of $27,449.10 or $638.35 per patient. A cost saving of $3.03 in statin therapy was realized for each dollar spent on MNT. We conclude that an average of 3 individualized dietitian visits of 1 hour each over an 8-week period has a beneficial effect in treating patients with combined hyperlipidemia and recommend consideration of MNT as a cost-effective intervention.

Niacin accelerates intracellular ApoB degradation by inhibiting triacylglycerol synthesis in human hepatoblastoma (HepG2) cells.

The mechanism by which the potent drug niacin decreases apoB-containing atherogenic lipoproteins and prevents coronary disease is unclear. Utilizing human hepatoblastoma (HepG2) cells as an in vitro model, we have examined the effect of niacin on intracellular degradation of apoB and the regulatory mechanisms involved in apoB processing. Niacin significantly increased apoB degradation in a dose- and time-dependent manner. Treatment of HepG2 cells with calpain inhibitor I [N-acetyl-leucyl-leucyl-norleucinal (ALLN), an inhibitor of certain protease-mediated apoB degradation], did not alter niacin-induced apoB degradation. Niacin decreased inhibition of oleate-mediated apoB degradation. Niacin dose-dependently inhibited the synthesis of both fatty acids and triacylglycerol (TG) by 20% to 40% as determined by the incorporation of 14C-acetate and 3H-glycerol into fatty acids and TG, respectively. Incubation of HepG2 cells with niacin significantly inhibited (by 12% to 15%) fatty acid esterification to produce TG as assessed by the incorporation of 3H-oleic acid into TG. 14C-acetate incorporation into cholesterol and phospholipids was unchanged. The activity of microsomal triglyceride transfer protein (MTP), a carrier protein for lipids, was not altered by pretreatment of cells with niacin. ApoB mRNA expression and 125I-LDL protein uptake were also unchanged. These data indicate that niacin accelerates hepatic intracellular post-translational degradation of apoB by selectively reducing triglyceride synthesis (through inhibiting both fatty acid synthesis and fatty acid esterification to produce TG) without affecting ALLN-inhibitable protease- or MTP-mediated intracellular apoB processing, resulting in decreased apoB secretion and hence lower circulating levels of the atherogenic lipoproteins.

Medical nutrition therapy lowers serum cholesterol and saves medication costs in men with hypercholesterolemia.

This study was designed to evaluate whether medical nutrition therapy administered by registered dietitians could lead to a beneficial clinical and cost outcome in men with hypercholesterolemia. Ninety-five subjects participating in a cholesterol-lowering drug study took part in an 8-week nutrition intervention program before initiating treatment with a cholesterol-lowering medication, Patient records were reviewed via a retrospective chart review to determine plasma lipid levels at the beginning and end of the program and the number and length of sessions with a dietitian. Complete information was available for 74 subjects aged 60.8 n+/- 9.8 years (mean +/- SD). Medical nutrition therapy lowered total serum cholesterol levels 13% (P < .001), low-density lipoprotein cholesterol (LDL-C) 15% (P < .0001), triglyceride 11% (P < .05), and high-density lipoprotein-cholesterol (HDL-C) 4% (P < .05). Total dietitian intervention time was 144 +/- 21 minutes (range = 120 to 180 minutes) in 2.8 +/- 0.7 sessions (range = 2 to 4) during 6.81 +/- 0.7 weeks of medical nutrition therapy (range = 6 to 8 weeks). Analysis of covariance was conducted to examine whether mean change in LDL-C differed by number of dietitian visits. Results showed a marginal difference between the number of dietitian visits and change in LDL-C (f = 2.6, P < .084). However, the magnitude of LDL-C reduction was significantly higher with 4 dietitian visits (180 minutes) than with 2 visits (120 minutes) (21.9% vs 12.1%; P = .027). Lipid drug eligibility was obviated in 34 of 67 (51%) subjects per the National Cholesterol Treatment Program guidelines algorithm. The estimated annualized cost savings from the avoidance of lipid medications was $60,561.68. Therefore, we conclude that 3 or 4 individualized dietitian visits of 50 minutes each over 7 weeks are associated with a significant serum cholesterol reduction and a savings of health care dollars.

Estradiol stimulates apolipoprotein A-I- but not A-II-containing particle synthesis and secretion by stimulating mRNA transcription rate in Hep G2 cells.

Estrogen therapy increases plasma HDL levels, which may reduce cardiovascular risk in postmenopausal women. The mechanism of action of estrogen in influencing various steps in hepatic HDL and apolipoprotein (apo) A-I synthesis and secretion are not fully understood. In this study, we have used the human hepatoblastoma cell line (Hep G2) as an in vitro model system to delineate the effect of estradiol on multiple regulatory steps involved in hepatic HDL metabolism. Incubation of Hep G2 cells with estradiol resulted in the following statistically significant findings: (1) increased accumulation of apoA-I in the medium without affecting uptake/removal of radiolabeled HDL-protein; (2) accelerated incorporation of [3H]leucine into apoA-I; (3) selective increase in [3H]leucine incorporation into lipoprotein (LP) A-I but not LP A-I+A-II HDL particles (HDL particles without and with apoA-II, respectively); (4) increased ability of apoA-I-containing particles to efflux cholesterol from fibroblasts; (5) stimulated steady state apoA-I but not apoA-II mRNA expression; and (6) increased newly transcribed apoA-I mRNA message without effect on apoA-I mRNA half-life. The data indicate that estradiol stimulates newly transcribed hepatic apoA-I mRNA, resulting in a selective increase in LP A-I, a subfraction of HDL that is associated with decreased atherosclerotic cardiovascular disease, especially in premenopausal women.

Mechanistic studies of high-density lipoproteins.

There is increasing evidence that high-density lipoprotein (HDL) and its subfractions are protective against atherosclerotic cardiovascular disease. Physical exercise, weight reduction, smoking cessation, diabetes mellitus control, and specific drugs, including niacin, fibrates, and estrogens, are effective methods to increase HDL levels. Niacin is the oldest and most powerful clinical agent for raising HDL levels. Niaspan, an extended-release niacin formulation, is as potent as immediate-release niacin in increasing levels of HDL cholesterol; subfractions HDL2 and HDL3; apolipoprotein A-I, the major protein of HDL, and its cardioprotective subfraction lipoprotein A-I. Recent research from our laboratory suggests a novel mechanism by which niacin inhibits hepatic removal of HDL-apoprotein A-I without interfering with the removal of cholesterol carried by HDL, thus augmenting reverse cholesterol transport. Other mechanistic studies indicate that fibrates and estrogens stimulate the synthesis and production of HDL-apoprotein A-I. Because niacin decreases HDL-apoprotein A-I removal, and fibrates and estrogens increase HDL-apoprotein A-I production, combinations of niacin with these agents may raise HDL levels more than fibrates or estrogens alone.

Niacin decreases removal of high-density lipoprotein apolipoprotein A-I but not cholesterol ester by Hep G2 cells. Implication for reverse cholesterol transport.

Niacin (nicotinic acid) is the most potent clinically used agent for increasing plasma HDL and apolipoprotein (apo) A-I. The mechanism by which niacin increases apoA-I is not clearly understood. We have examined the effect of niacin on the hepatic production and removal of apoA-I using Hep G2 cells as an in vitro model. Incubation of Hep G2 cells with niacin resulted in increased accumulation of apoA-I in the medium in a dose-dependent manner. Incorporation of [3H]leucine and [35S]methionine into apoA-I and apoA-I mRNA expression was unchanged by niacin, suggesting that it did not affect apoA-I de novo synthesis. Uptake of radiolabeled HDL protein and HDL apoA-I by Hep G2 cells was significantly reduced to as much as 82.9 +/- 2.2% (P = .04) and 84.2 +/- 2.8% (P = .02), respectively, of the baseline with increasing concentrations of niacin (0 to 3.0 mmol/L). Specific 125I-HDL protein uptake measured with a 50-fold excess of unlabeled HDL was reduced to as much as 78.3 +/- 4.8% (P = .005) in niacin-treated cells. The uptake of labeled cholesterol esters in HDL was unaffected by niacin. Niacin also effected a similar decrease in HDL protein uptake, but not cholesterol esters, from apoA-I-containing HDL particles isolated by immunoaffinity. The conditioned medium obtained from Hep G2 cells incubated with niacin significantly (P = .002) increased cholesterol efflux from cultured human fibroblasts. These data indicate a novel mechanism whereby niacin selectively decreases hepatic removal of HDL apoA-I but not cholesterol esters, thereby increasing the capacity of retained apoA-I to augment reverse cholesterol transport.

Cholesterol and atherosclerosis: a contemporary perspective.

Monumental advances in the field of lipid metabolism and its relationship to atherosclerotic cardiovascular disease have been achieved during the last half century. Epidemiologic studies have defined lipid disorders as highly significant independent risk factors for coronary heart disease, along with diabetes mellitus, hypertension and smoking. Primary and secondary prevention studies including the Coronary Primary Prevention Trial, Helsinki Heart Study, and the Coronary Drug Project have shown that lowering the atherogenic low density lipoproteins (LDL) and very low density lipoproteins (VLDL) whilst raising the high density lipoproteins (HDL) significantly decreases the risk for coronary disease. Striking evidence that aggressive therapy (to sharply lower LDL and raise HDL with newer drugs) prevents progression and induces regression of coronary narrowing has been obtained in numerous recent studies using quantitative coronary arteriography. An interesting and unexpected lesson learned from these arteriographic studies was that a highly significant reduction within months in several studies in coronary events was out of proportion to improvements in luminal narrowing. Recently, three major clinical trials to assess the effects of cholesterol reduction by the newly discovered HMG CoA reductase inhibitors (statins) have been published. Pravastatin significantly reduced coronary events in hypercholesterolemic patients [mean LDL-Chol. = 5.0 mM/L (192 mg/dl)] without a history of myocardial infarction. In a secondary prevention study, simvastatin also reduced coronary complications in hypercholesterolemic patients [mean LDL-Chol. = 4.9 mM/L (190 mg/dl)] with pre-existing coronary disease. Very recently, pravastatin treatment significantly reduced coronary events and stroke in patients with a history of myocardial infarction and average cholesterol levels [mean LDL-Chol. = 3.6 mM/L (139 mg/dl)], representing the majority of patients with coronary disease. In all these studies, reduction in cardiovascular events was approximately one-third. In subgroup analyses, men, women, elderly, smokers and hypertensives benefited from cholesterol lowering. There was no significant increase in non-cardiovascular causes of death. In the United States of America, the National Cholesterol Education Program (NCEP) Adult Treatment Panel, representing major health organizations, developed national guidelines on the detection, evaluation and treatment of high blood cholesterol in adults. In a given patient, the Panel recognizes the importance of weighing all cardiovascular disease risk factors including age (men > 45 years, postmenopausal women), family history of premature coronary disease, smoking, hypertension, diabetes and HDL-Cholesterol (< 35 mg/dl) in determining how aggressive therapy should be. The patient with manifest coronary heart disease (CHD) is given a special position as such patients are at highest risk for recurrent events. Major goals of therapy are to lower the LDL-Cholesterol to 2.6 mM/L (< 100 mg/dl) in the CHD patient. In non-CHD patients with two or more risk factors, the LDL-Cholesterol goal is 3.4 mM/L (130 mg/dl). In those with fewer risk factors, the goal is 4.2 mM/L (160 mg/dl). These guidelines should be modified as appropriate for Singapore. Patients with elevated triglycerides usually have low HDL-Cholesterol levels and often represent a heterogeneous group who may have other concurrent abnormalities including the presence of small dense LDL, insulin resistance, hypertension, obesity, overt diabetes and combined hyperlipidemia. Such patients merit individualized treatment. The prevalence of this syndrome may be more common in Singapore and requires further investigation. Current therapeutic guidelines emphasize the need for weight loss and dietary restriction of total and especially saturated fat (< 7% to 10% total calories), cholesterol (< 200 to 300 mg/day), and exercise. (ABSTRACT TRUNCATED)

Effect of pharmaceutical care on optimum colestipol treatment in elderly hypercholesterolemic veterans.

We conducted a prospective trial to determine whether a formal, integrated pharmaceutical care plan can enhance patient acceptance and compliance with colestipol therapy and improve outcomes. Forty patients with hypercholesterolemia were equally divided and assigned to either a usual care or pharmaceutical care group. In the pharmaceutical care group compared with the usual care group, after 52 weeks, colestipol therapy resulted in a greater reduction in total cholesterol (12.5% vs 7.3%), low-density lipoprotein cholesterol (LDL-C; 16% vs 9.4%), and LDL-C:high-density lipoprotein cholesterol (HDL-C) ratio (24.4% vs 12.2%, p < 0.05). The percentage of patients who achieved their LDL-C goal at week 52 was much greater in the pharmaceutical care group (29.4%) than in the usual care group (5.0%, p < 0.05). Co-management by a physician and a pharmacist of hypercholesterolemic veterans treated with colestipol can enhance patient acceptance of the drug, LDL-C reduction, and achievement of therapeutic goals.

Effect of serum subfractions from peritoneal dialysis patients on Hep-G2 cell apolipoprotein A-I and B metabolism.

We previously showed that uremic serum subfractions isolated from hemodialysis (HD) patients inhibited the production of apolipoprotein (apo) A-I by human hepatoblastoma cells, Hep-G2. Because of the reported differences in atherogenic cardiovascular mortality between HD and peritoneal dialysis (PD) patients, we examined the effect of similar subfractions from PD patients on apo A-I and apo B synthesis. After obtaining informed consent, serum samples from five normal subjects and nine stable PD patients were applied to Sephadex G-25 columns to obtain the serum subfractions used in the various experiments. Sephadex G-25 chromatograms of PD sera showed a broad peak from fractions 30 through 60 (molecular wt 500 to 2000 Da). Control serum showed no peak in this region. PD serum subfractions decreased apo A-I synthesis, secretion, and apo A-I mRNA expression by Hep-G2 cells when compared to subfractions from control subjects. Cholesterol efflux studies showed that conditioned media obtained from Hep-G2 cells incubated with PD serum subfractions inhibited cholesterol efflux from fibroblasts, suggesting a biologically-significant decrease in apo A-I synthesis. PD serum subfractions increased protein synthesis and mRNA expressions of apo B by Hep-G2 cells. Therefore, serum subfractions obtained from PD patients decreased apo A-I and increased apo B synthesis, findings consistent with their serum lipoprotein profiles suggesting that a biologically-active component in these subfractions could contribute to the risk of atherogenic cardiovascular disease in PD.

Gemfibrozil stimulates apolipoprotein A-I synthesis and secretion by stabilization of mRNA transcripts in human hepatoblastoma cell line (Hep G2).

Gemfibrozil is a widely used drug that elevates plasma HDL and lowers triglycerides and LDL. The mechanism of action of this pharmacological agent on HDL metabolism is not established. Since the liver is the major organ involved in HDL production and removal, we assessed the effect of gemfibrozil on the modulation of apoA-I (a major protein of HDL)-containing particles by a human hepatoblastoma cell line (Hep G2). Incubation of Hep G2 cells with gemfibrozil resulted in the following statistically significant findings: (1) increased accumulation of apoA-I in the medium without affecting uptake of radiolabeled HDL-protein or HDL-apoA-I; (2) accelerated incorporation of [3H]leucine and [35S]methionine into apoA-I; (3) equivalent increases in [3H]leucine incorporation into HDL particles without and with apoA-II (LpA-I and LpA-I+A-II, respectively); (4) equal efflux of fibroblast cholesterol by harvested LpA-I and LpA-I+A-II particles; (5) increased steady state apoA-I mRNA without affecting apoA-I transcription; and (6) increased apoA-I mRNA half-life (2.2-fold). These data indicate that gemfibrozil stabilizes apoA-I mRNA transcripts, resulting in increased translation of functional apoA-I-containing particles capable of effluxing cellular cholesterol, thus defining a major mechanism by which gemfibrozil increases HDL.

Fish oil as an adjuvant in the treatment of hypertension.

STUDY OBJECTIVE: To evaluate the effects of omega-3 fatty acids on blood pressure control and lipid levels. DESIGN: Double-blind, placebo-controlled, randomized study. SETTING: Veterans Affairs Medical Center teaching hospital. PATIENTS: Twenty-one men whose blood pressure was not optimally controlled with antihypertensive agents, who met the inclusion criteria. INTERVENTIONS: Patients were randomized to receive either fish oil (4.5 g omega-3 fatty acids/day) or placebo. MEASUREMENTS AND MAIN RESULTS: Blood pressure readings were taken at baseline, and 4 and 8 weeks. Sitting systolic and diastolic blood pressures were significantly reduced in the fish oil group at both week 4 (148/97 to 132/90, p <0.05) and week 8 (148/97 to 134/91, p <0.05). Sitting diastolic blood pressure was significantly reduced in the placebo group at week 8 (94 to 88, p <0.05). There was no difference in percentage change of sitting systolic and diastolic pressures at week 8 comparing the placebo group (-6.4% and -6.3%, respectively) and the fish oil group (-8.8% and -6.6%, respectively). Triglyceride levels (-40.9%, p <0.05) and platelet counts (-8.7%, p <0.05) were significantly reduced at 4 weeks, and low-density lipoprotein (LDL) cholesterol levels were significantly increased both at 4 and 8 weeks (13.5% and 19.1%, respectively) in the fish oil group. CONCLUSION: Adjunctive fish oil supplementation did not substantially augment blood pressure lowering in treated hypertensive men with suboptimally controlled blood pressure. Effects on plasma lipid values were mixed, with an increase in LDL cholesterol and a decrease in plasma triglyceride levels.

Noninvasive tracking of coronary atherosclerosis by electron beam computed tomography: rationale and design of the Felodipine Atherosclerosis Prevention Study (FAPS).

The Felodipine Atherosclerosis Prevention Study is designed to evaluate the efficacy of the calcium antagonist felodipine ER and combined felodipine/simvastatin therapy on retarding the progression of atherosclerosis, estimated by serial changes in coronary calcium evaluated by noninvasive electron beam computed tomography. Subjects include 180 men and women aged 40 to 69 and 50 to 69 years, respectively, with moderate type IIa dyslipidemia, with either cardiovascular disease or risk factors. All subjects receive simvastatin lipid-lowering therapy, and are randomized either to felodipine or placebo for a treatment period of 2 years. Monitoring of blood chemistry, measures of lipids and apolipoproteins, blood pressure, evaluation of symptoms, and interim clinical event monitoring are done at routine follow-up visits. Baseline and 2-year follow-up electron beam computed tomography, measuring changes in total calcium score, area, and mass, evaluate the effects of intervention on the progression of calcified atherosclerosis. The results from the Felodipine Atherosclerosis Prevention Study will provide valuable information about the effect of felodipine alone and in combination with simvastatin on progression of calcified atherosclerosis evaluated noninvasively.