HDL (High-Density Lipoprotein) Remodeling and Magnetic Resonance Imaging-Assessed Atherosclerotic Plaque Burden: Study in a Preclinical Experimental Model.

OBJECTIVE: HDL (high-density lipoprotein) role in atherosclerosis is controversial. Clinical trials with CETP (cholesterylester transfer protein)-inhibitors have not provided benefit. We have shown that HDL remodeling in hypercholesterolemia reduces HDL cardioprotective potential. We aimed to assess whether hypercholesterolemia affects HDL-induced atherosclerotic plaque regression. Approach and Results: Atherosclerosis was induced in New Zealand White rabbits for 3-months by combining a high-fat-diet and double-balloon aortic denudation. Then, animals underwent magnetic resonance imaging (basal plaque) and randomized to receive 4 IV infusions (1 infusion/wk) of HDL isolated from normocholesterolemic (NC-HDL; 75 mg/kg; n=10), hypercholesterolemic (HC-HDL; 75 mg/Kg; n=10), or vehicle (n=10) rabbits. Then, animals underwent a second magnetic resonance imaging (end plaque). Blood, aorta, and liver samples were obtained for analyses. Follow-up magnetic resonance imaging revealed that NC-HDL administration regressed atherosclerotic lesions by 4.3%, whereas, conversely, the administration of HC-HDLs induced a further 6.5% progression (P<0.05 versus basal). Plaque characterization showed that HC-HDL administered animals had a 2-fold higher lipid and cholesterol content versus those infused NC-HDL and vehicle (P<0.05). No differences were observed among groups in CD31 levels, nor in infiltrated macrophages or smooth muscle cells. Plaques from HC-HDL administered animals exhibited higher Casp3 (caspase 3) content (P<0.05 versus vehicle and NC-HDL) whereas plaques from NC-HDL infused animals showed lower expression of Casp3, Cox1 (cyclooxygenase 1), inducible nitric oxide synthase, and MMP (metalloproteinase) activity (P<0.05 versus HC-HDL and vehicle). HDLs isolated from animals administered HC-HDL displayed lower antioxidant potential and cholesterol efflux capacity as compared with HDLs isolated from NC-HDL-infused animal and vehicle or donor HDL (P<0.05). There were no differences in HDL-ApoA1 content, ABCA1 (ATP-binding cassette transporter A1) vascular expression, and SRB1 (scavenger receptor B1) and ABCA1 liver expression. CONCLUSIONS: HDL particles isolated from a hypercholesterolemic milieu lose their ability to regress and stabilize atherosclerotic lesions. Our data suggest that HDL remodeling in patients with co-morbidities may lead to the loss of HDL atheroprotective functions.

Reconstituted High-density Lipoprotein Therapy Improves Survival in Mouse Models of Sepsis.

BACKGROUND: High-density lipoproteins exert pleiotropic effects including antiinflammatory, antiapoptotic, and lipopolysaccharide-neutralizing properties. The authors assessed the effects of reconstituted high-density lipoproteins (CSL-111) intravenous injection in different models of sepsis. METHODS: Ten-week-old C57BL/6 mice were subjected to sepsis by cecal ligation and puncture or intraperitoneal injection of Escherichia coli or Pseudomonas aeruginosa pneumonia. CSL-111 or saline solution was administrated 2 h after the sepsis. Primary outcome was survival. Secondary outcomes were plasma cell-free DNA and cytokine concentrations, histology, bacterial count, and biodistribution. RESULTS: Compared with saline, CSL-111 improved survival in cecal ligation and puncture and intraperitoneal models (13 of 16 [81%] survival rate vs. 6 of 16 [38%] in the cecal ligation and puncture model; P = 0.011; 4 of 10 [40%] vs. 0 of 10 [0%] in the intraperitoneal model; P = 0.011). Cell-free DNA concentration was lower in CSL-111 relative to saline groups (68 [24 to 123] pg/ml vs. 351 [333 to 683] pg/ml; P < 0.001). Mice injected with CSL-111 presented a decreased bacterial count at 24 h after the cecal ligation and puncture model both in plasma (200 [28 to 2,302] vs. 2,500 [953 to 3,636] colony-forming unit/ml; P = 0.021) and in the liver (1,359 [360 to 1,648] vs. 1,808 [1,464 to 2,720] colony-forming unit/ml; P = 0.031). In the pneumonia model, fewer bacteria accumulated in liver and lung of the CSL-111 group. CSL-111-injected mice had also less lung inflammation versus saline mice (CD68+ to total cells ratio: saline, 0.24 [0.22 to 0.27]; CSL-111, 0.07 [0.01 to 0.09]; P < 0.01). In all models, no difference was found for cytokine concentration. Indium bacterial labeling underlined a potential hepatic bacterial clearance possibly promoted by high-density lipoprotein uptake. CONCLUSIONS: CSL-111 infusion improved survival in different experimental mouse models of sepsis. It reduced inflammation in both plasma and organs and decreased bacterial count. These results emphasized the key role for high-density lipoproteins in endothelial and organ protection, but also in lipopolysaccharide/bacteria clearance. This suggests an opportunity to explore the therapeutic potential of high-density lipoproteins in septic conditions.

ABCA1/ApoE/HDL Pathway Mediates GW3965-Induced Neurorestoration After Stroke.

BACKGROUND AND PURPOSE: ATP-binding cassette transporter A1 (ABCA1) is a major reverse cholesterol transporter and plays critical role in the formation of brain high-density lipoprotein (HDL) cholesterol. Apolipoprotein E (ApoE) is the most abundant apolipoprotein and transports cholesterol into cells in brain. ABCA1 and ApoE are upregulated by liver-X receptors. Activation of liver-X receptors has neurorestorative benefit for stroke. The current study investigates whether ABCA1/ApoE/HDL pathway mediates GW3965, a synthetic dual liver-X receptor agonist, induced neurorestoration after stroke. METHODS: Middle-aged male specific brain ABCA1-deficient (ABCA1-B/-B) and floxed-control (ABCA1fl/fl) mice were subjected to distal middle-cerebral artery occlusion (dMCAo) and gavaged with saline or GW3965 (10 mg/kg) or intracerebral infusion of artificial cerebrospinal fluid or human plasma HDL3 in ABCA1-B/-B stroke mice, starting 24 hours after dMCAo and daily until euthanization 14 days after dMCAo. RESULTS: No differences in the blood level of total cholesterol and triglyceride and lesion volume were found among the groups. Compared with ABCA1fl/fl ischemic mice, ABCA1-B/-B ischemic mice exhibited impairment functional outcome and decreased ABCA1/ApoE expression and decreased gray/white matter densities in the ischemic boundary zone 14 days after dMCAo. GW3965 treatment of ABCA1fl/fl ischemic mice led to increased brain ABCA1/ApoE expression, concomitantly to increased blood HDL, gray/white matter densities and oligodendrocyte progenitor cell numbers in the ischemic boundary zone, as well as improved functional outcome 14 days after dMCAo. GW3965 treatment had negligible beneficial effects in ABCA1-B/-B ischemic mice. However, intracerebral infusion of human plasma HDL3 significantly attenuated ABCA1-B/-B-induced deficits. In vitro, GW3965 treatment (5 µM) increased ABCA1/synaptophysin level and neurite/axonal outgrowth in primary cortical neurons derived from ABCA1fl/fl embryos, but not in neurons derived from ABCA1-B/-B embryos. HDL treatment (80 µg/mL) attenuated the reduction of neurite/axonal outgrowth in neurons derived from ABCA1-B/-B embryos. CONCLUSIONS: ABCA1/ApoE/HDL pathway, at least partially, contributes to GW3965-induced neurorestoration after stroke.

Homozygous autosomal dominant hypercholesterolaemia: prevalence, diagnosis, and current and future treatment perspectives.

PURPOSE OF REVIEW: Homozygous autosomal dominant hypercholesterolemia (hoADH) is a rare genetic disorder caused by mutations in LDL receptor, apolipoprotein B, and/or proprotein convertase subtilisin-kexin type 9. Both the genetic mutations and the clinical phenotype vary largely among individual patients, but patients with hoADH are typically characterized by extremely elevated LDL-cholesterol (LDL-C) levels, and a very high-risk for premature cardiovascular disease. Current lipid-lowering therapies include bile acid sequestrants, statins, and ezetimibe. To further decrease LDL-C levels in hoADH, lipoprotein apheresis is recommended, but this therapy is not available in all countries. RECENT FINDINGS: Recently, the microsomal triglyceride transfer protein inhibitor lomitapide and the RNA antisense inhibitor of apolipoprotein B mipomersen were approved by the Food and Drug Administration/European Medicine Agency and the Food and Drug Administration, respectively. Several other LDL-C-lowering strategies and therapeutics targeting the HDL-C pathway are currently in the clinical stage of development. SUMMARY: Novel therapies have been introduced for LDL-C-lowering and innovative drug candidates for HDL-C modulation for the treatment of hoADH. Here, we review the current available literature on the prevalence, diagnosis, and therapeutic strategies for hoADH.

Controversies on HDL: should it be a target biomarker in patients with lipid disorders?

Low-density lipoprotein (LDL) cholesterol lowering with statins have had a profound impact on cardiovascular (CV) event rates and accordingly have become an integral component of strategies designed to reduce CV risk. The finding of a residual clinical risk, despite LDL cholesterol lowering, supports the need to develop additional therapeutic strategies for CV prevention. Numerous lines of evidence suggest that targeting the protective properties of high-density lipoproteins (HDL) may be beneficial. Disappointing results from recent reports of HDL genetics and raising agents and clinical events has fueled considerable debate as to whether attempts to target HDL will be of clinical benefit or futility. This review will reflect on challenges faced in developing new effective HDL targeted therapies.

Consuming a diet complying with front-of-pack label criteria may reduce cholesterol levels: a modeling study.

BACKGROUND/OBJECTIVES: Front-of-pack nutrition labels can help consumers to make healthier choices and stimulate healthier product development. This is the first modeling study to investigate the potential impact on cholesterol levels of consuming a diet consisting of products that comply with the criteria for a 'healthier choice logo'. SUBJECTS/METHODS: National food consumption and food composition data were used to estimate the nutrient intake of the Dutch adult population (18-70 years) before and after replacing foods that did not comply with the choices front-of-pack label criteria. Different scenarios were established. The difference in cholesterol levels in the Dutch population was assessed before and after replacement by means of equations from meta-analyses that calculate how blood lipids change when diet composition changes. RESULTS: After replacing non-complying products with products, which comply with the label's criteria (maximum scenario), saturated fatty acids median intake reduced from 14.5 to 9.8 en%. Trans-fatty acids reduced from 0.95 to 0.57 en%. The average predicted changes in low-density lipoprotein and total cholesterol levels were -0.25 and -0.31 mmol/l, respectively. Because high-density lipoprotein (HDL) cholesterol levels reduced as well (-0.05 mmol/l), overall, the result was a slightly positive change in the total cholesterol/HDL ratio (-0.03). CONCLUSIONS: Our findings suggest that the consumption of foods complying with the criteria for a front-of-pack label could contribute moderately to cardiovascular risk reduction via influencing blood lipids. These findings were independent of other potential effects on related health outcomes.

Reconstituted HDL elicits marked changes in plasma lipids following single-dose injection in C57Bl/6 mice.

High-density lipoprotein (HDL)-targeting therapies, including reconstituted HDL (rHDL), are attractive agents for treating dyslipidemia and atherosclerosis, as they may increase HDL levels and enhance therapeutic activities associated with HDL, including reverse cholesterol transport (RCT). Using CSL-111, a rHDL consisting of native human apolipoprotein AI (hApoAI) and phospholipids, we characterized the acute effects of rHDL administration in C57Bl/6 mice to (i) further our understanding of the mechanism of action of rHDL, and (ii) evaluate the usefulness of the mouse as a preclinical model for HDL-targeting therapies. After a single injection of CSL-111, there was a dose- and time-dependent increase of hApoAI, human pre-ß HDL, total cholesterol, and triglycerides in serum, consistent with the effects of CSL-111 in humans. However, unlike in humans, there was no measurable increase in cholesteryl esters. Evaluated ex vivo, the ATP binding cassette A1 (ABCA1)- and scavenger receptor type BI (SR-BI)-dependent cholesterol efflux capacity of serum from CSL-111-treated mice was increased compared with serum from vehicle-treated animals. Fractionation by size exclusion chromatography of lipoproteins in serum from treated mice revealed hApoAI in particles the size of endogenous HDL and slightly larger, cholesterol-enriched particles of all sizes, including sizes distinct from endogenous HDL or CSL-111 itself, and triglyceride-enriched particles the size of very-low-density lipoprotein (VLDL). These results suggest that in mouse blood CSL-111 is remodeled and generates enhanced cholesterol efflux capacity which increases mobilization of free cholesterol from peripheral tissues. Our findings complement the previous reports on CSL-111 in human participants and provide data with which to evaluate the potential utility of mouse models in mechanistic studies of HDL-targeting therapies.

Emerging high-density lipoprotein infusion therapies: fulfilling the promise of epidemiology?

High-density lipoprotein (HDL) plays a key role in reverse cholesterol transport but also activates nitric oxide synthase and stimulates prostacyclin release, enhances endothelial repair, inhibits cell adhesion molecule expression on vascular endothelium and monocyte recruitment into the arterial wall, and exerts antithrombotic effects. In experimental animals, infusions of HDL or apolipoprotein A-1 (apoA-1) halt the progression or induce regression of atherosclerosis, with favorable effects on plaque composition. Remarkably, a benefit is observed after a single infusion. In a pilot study, weekly infusions of ETC-216, a formulation of recombinant apoA-1 Milano, were administered at two doses for 5 weeks to patients beginning within 2 weeks of an acute coronary syndrome (ACS). Among the 47 patients completing the study, percent atheroma volume by intracoronary ultrasound was reduced in the combined active treatment groups but not in the placebo group. In a larger trial, the Effect of rHDL on Atherosclerosis-Safety and efficacy (ERASE), 183 post-ACS patients were randomized to 4 weekly infusions of placebo or one of two doses of CSL-111, which consists of apoA-1 derived from human plasma and combined with soybean phosphatidylcholine. The greater dose was discontinued because of a high incidence of hepatic enzyme elevation. Among the 136 patients with evaluable end point data, percent change in atheroma volume, the primary endpoint, improved significantly in the CSL-111 group but not in the placebo group. The secondary end points of plaque characterization indices and quantitative coronary angiographic changes both improved significantly in the CSL-111 group compared with the group receiving placebo. Taken together, this evidence suggests that infusions of HDL or apoA-1 may reduce events, particularly among patients with ACS.

Lipoproteínas de alta densidad y regresión de la arteriosclerosis: desde la teoría hasta la imagen / High-density lipoprotein and arteriosclerosis regression: from theory to imaging studies

La aterotrombosis (aterosclerosis y sus complicaciones trombóticas) se caracteriza por el acúmulo de lípidos y células inflamatorias en la pared de vasos de mediano y gran calibre. Las lipoproteínas asociadas al colesterol juegan un papel central en la homeostasis de la placa de ateroma, siendo la lipoproteína de alta densidad (HDL) la responsable de la salida del colesterol y de su transporte al hígado para su ulterior excreción. El desarrollo de nuevas técnicas de imagen ha permitido documentar de forma longitudinal los cambios en el volumen de placa. Si bien no hay evidencia directa, datos indirectos confirman que la regresión del volumen de la placa puede asociarse a una disminución de episodios cardiovasculares. Por este motivo, la regresión de la placa/ausencia de progresión se utiliza como un objetivo subrogado con frecuencia creciente. De todas las terapias antiateroscleróticas testadas, el incremento de la HDL por diferentes abordajes es el que ha resultado más eficaz en regresar el volumen de placas de ateroma (AU)

Atherothrombosis (atherosclerosis and its thrombotic complications) is characterized by the accumulation of lipids and inflammatory cells in the walls of intermediate- and largecaliber vessels. The lipoproteins associated with cholesterol play a central role in homeostasis of the atheroma plaque while high-density lipoproteins (HDL) play a critical role in cholesterol efflux and cholesterol transport to the liver for subsequent excretion The development of new imaging techniques has allowed changes in plaque volume to be documented longitudinally. Although there is no direct evidence, indirect data confirm that regression of plaque volume can be associated with a reduction in cardiovascular events. For this reason, plaque regression/absence of progression is increasingly used as a surrogate objective. Of all the antiatherosclerotic therapies tested, the increase in HDL by distinct approaches is the most effective in reducing atheroma plaque volumen (AU)

¿Hay evidencias de que la elevación del colesterol unido a lipoproteínas de alta densidad obtiene beneficio clínico? / Is there evidence that increasing high-density lipoprotein cholesterol has clinical benefits?

La relación entre valores reducidos de colesterol unido a lipoproteínas de alta densidad (cHDL) y un aumento de riesgo de desarrollo de aterosclerosis es incuestionable desde el punto de vista epidemiológico. La mayoría de los ensayos clínicos ha valorado elevaciones del cHDL sin estudiar los cambios en la funcionalidad de las HDL. Adicionalmente, los fármacos que se han empleado para elevar el cHDL tienen una eficacia limitada, así como efectos secundarios no deseados, pertenecen a grupos farmacológicos heterogéneos con efectos metabólicos variados y, en algunas ocasiones, han mostrado efectos cardiovasculares contraproducentes. Globalmente, puede considerarse que la elevación farmacológica de los valores de cHDL ha producido, hasta ahora, efectos protectores cardiovasculares escasos, muy inferiores a los esperables a partir de los datos epidemiológicos. La importante diana del cHDL necesita nuevas aproximaciones terapéuticas que consigan de modo efectivo una reducción significativa del riesgo vascular (AU)

The association between reduced levels of high-density lipoprotein cholesterol (HDL-c) and an increased risk of the development of atherosclerosis is unquestionable from an epidemiological point of view. Most clinical trials have evaluated HDL-c elevations without studying changes in the functionality of high-density lipoproteins. Additionally, the drugs used to increase HDL-c have limited efficacy as well as unwanted side effects, belong to heterogeneous pharmacological groups with varied metabolic effects, and have sometimes shown deleterious cardiovascular effects. Overall, pharmacological elevation of HDL-c has produced scarce protective cardiovascular effects to date, much lower than those expected from the epidemiological data. HDL-c, a major and elusive target, requires new therapeutic approaches to significantly reduce vascular risk (AU)

La elevación del colesterol unido a lipoproteínas de alta densidad: perspectiva futura. La CETP como diana terapéutica / Elevation of high-density lipoprotein cholesterol: future perspective. Cholesteryl ester transfer protein as a therapeutic target

La CETP (cholesteryl ester transfer protein) es la proteína responsable de la transferencia de lípidos neutros entre las lipoproteínas. La CETP juega un papel clave en la homeostasis del colesterol, especialmente en la redistribución de colesterol entre partículas y en el transporte reverso de colesterol, por lo que la modificación de su actividad puede modificar el desarrollo y la evolución de la ateromatosis. Los efectos de la inhibición de CETP incluyen: reducción de colesterol LDL y aumento del colesterol HDL y apo A-1, aumento en el tamaño de las partículas LDL y HDL, y reducción del colesterol en las partí- culas ricas en triglicéridos. En consonancia, la inducción de expresión de la actividad CETP en ratones aumenta la susceptibilidad a la aterosclerosis mientras que la inhibición de la actividad CETP en conejos tiende a reducir su desarrollo. Sin embargo, el papel de la inhibición de CETP en la ateromatosis en humanos está todavía por definir (AU)

Cholesteryl ester transfer protein (CETP) facilitates transfer of neutral lipids between lipoprotein classes. CETP plays a key role in cholesterol homeostasis, especially in the redistribution of cholesterol among particles and in reverse cholesterol transport. Consequently, modifying the activity of this protein could influence the development and progression of atheromatosis. The effects of inhibiting CETP include reductions in lowdensity lipoprotein (LDL)-cholesterol and cholesterol in triglyceride-rich particles and increases in high-density lipoprotein (HDL)-cholesterol, apolipoprotein A-1 and the size of LDL and HDL particles. The induction of expression of CETP activity in mice increases susceptibility to atherosclerosis, while inhibition of CETP activity in rabbits tends to reduce its development. However, the role of CETP inhibition in atheromatosis in humans remains to be established (AU)

Torcetrapib: una perspectiva histórica / Torcetrapib: a historical view

Diversos estudios experimentales han demostrado que las lipoproteínas de alta densidad (HDL) representan un grupo funcionalmente muy heterogéneo de partículas con diversos efectos antioxidantes, antiinflamatorios, que les confiere propiedades antiaterogénicas y antitrombóticas. En la actualidad, se dispone de potentes alternativas terapéuticas que permiten alcanzar cifras muy bajas de colesterol unido a lipoproteínas de baja densidad, y desde hace varios años están en continuo desarrollo y evaluación fármacos que permiten incrementos significativos de los valores de colesterol unido a HDL, con la intención de mejorar el perfil cardiovascular de los pacientes. Los inhibidores de la enzima colesterol- éster transferasa constituyen una opción terapéutica válida para este fin. A continuación se revisan los resultados de los primeros y principales ensayos clínicos que evalúan la eficacia de uno de estos fármacos (torcetrapib) así como los análisis pormenorizados realizados posteriormente por sus principales autores de las posibles explicaciones de los resultados clínicos desfavorables de éstos (AU)

Several experimental studies have shown that high-density lipoproteins are functionally a highly heterogeneous group of particles with varied antioxidant and antiinflammatory effects, conferring them with antiatherogenic and antithrombotic properties. Potent therapeutic alternatives are currently available that allow very low values of low-density lipoprotein to be achieved. For several years, drugs that allow significant increases in high-density lipoprotein cholesterol levels have been under continuous development and evaluation, with the aim of improving patients’ cardiovascular profiles. Cholesteryl ester transfer protein inhibitors are a suitable therapeutic option for this aim. We review the results of the first and main clinical trials evaluating the efficacy of one of these drugs (torcetrapib) as well as the detailed analyses subsequently performed by their main authors of the possible explanations for the unfavorable clinical results of these trials (AU)

High-density lipoprotein cholesterol as a risk factor and target of therapy after acute coronary syndrome.

Despite contemporary therapies for acute coronary syndrome (ACS), rates of morbidity and mortality remain high. Low levels of high-density lipoprotein (HDL) cholesterol are common among patients with ACS and predict risk for subsequent cardiovascular events, even on a background of intensive statin treatment. An extensive body of clinical and experimental data suggests that HDL cholesterol may promote favorable remodeling of coronary atherosclerotic plaque and ameliorate endothelial dysfunction, thrombotic tendency, inflammation, oxidative stress, and ischemia-reperfusion injury, which are all effects that might be beneficial after ACS. Clinical trials are in progress to test the hypothesis that strategies to raise levels of HDL cholesterol will reduce risk after ACS.

Usefulness of statin-ezetimibe combination to reduce the care gap in dyslipidemia management in patients with a high risk of atherosclerotic disease.

Lowering of low-density lipoprotein (LDL) cholesterol is a fundamental step in the comprehensive management of patients at high risk for cardiovascular events. The combination of a statin with ezetimibe usually provides additional LDL cholesterol lowering compared to statin monotherapy. This open-label observational study evaluated the impact of a 26-week treatment program with uptitration of statin dosages and incorporation of ezetimibe 10 mg therapy in 2,577 men and women (median age 64 years) with hypercholesterolemia and an LDL cholesterol level >2.5 mmol/L (97 mg/dl). Attainment of an LDL cholesterol target of 2.5 mmol/L (97 mg/dl) increased with consecutive visits (63%, 67%, and 71% at the second, third, and final visits, respectively). Current guideline-recommended LDL cholesterol value <2.0 mmol/L (77 mg/dl) was achieved by 36%, 40%, and 41% of the group at the same consecutive follow-up sessions. Median LDL cholesterol decreased from 3.0 mmol/L (116 mg/dl) at baseline to 2.1 mmol/L (81 mg/dl) at the end of the 26-week monitoring period. Favorable changes were concomitantly observed for median total cholesterol (5.1 to 4.1 mmol/L [197 to 159 mg/dl]), total cholesterol/high-density lipoprotein cholesterol ratio (4.2 to 3.3), and triglyceride (1.6 to 1.4 mmol/L [142 to 124 mg/dl]). Of those who attended visit 4, 48% exhibited LDL cholesterol lowering of > or =1 mmol/L (39 mg/dl) compared to baseline levels. In conclusion, an algorithm-based statin uptitration/ezetimibe combination regimen is useful to increase LDL cholesterol lowering where statin monotherapy has not achieved target lipid values.

Effect of niacin on LXRalpha and PPARgamma expression and HDL-induced cholesterol efflux in adipocytes of hypercholesterolemic rabbits.

BACKGROUND: Adipose tissue contains a large amount of cholesterol and performs a buffer function for circulating cholesterol. Liver X receptors (LXR) alpha and peroxisome proliferator-activated receptor gamma (PPARgamma) might play a significant role in adipocyte cholesterol metabolism through mediation of cholesterol efflux. The aim of this study was to evaluate the effect of niacin on LXRalpha and PPARgamma expression and HDL-induced cholesterol efflux in adipocytes from hypercholesterolemic rabbits. METHODS: Twelve rabbits fed with high-cholesterol diet for 8 weeks were randomly divided into two groups: (1) high cholesterol group (n=6): maintained high cholesterol diet for 6 weeks; (2) niacin group (n=6): the same cholesterol diet plus niacin (200 mg/kg/d) for 6 weeks. Control group (n=6) was fed with normal diet for 14 weeks. Subcutaneous adipose was collected for adipocyte culture. Reverse transcription polymerase chain reaction (RT-PCR) was used to evaluate adipocytes LXRalpha mRNA expressions. Cholesterol efflux rate was determined through measuring release of radioactivity from (3)H-cholesterol prelabeled cells into medium containing high-density lipoprotein (HDL). The direct effect of niacin on LXRalpha and PPARgamma mRNA expression in primary rabbit adipocytes was assayed. RESULTS: High cholesterol diet resulted in decreased LXRalpha mRNA expressions and reduced HDL-induced cholesterol efflux rate in adipocytes. Six weeks of niacin treatment significantly enhanced the cholesterol efflux from adipocytes, which was related to the increased mRNA expressions of LXRalpha (r=0.71, P<0.05). In in vitro study, niacin dose-dependently stimulated LXRalpha and PPARgamma mRNA expression in cultured adipocytes. And various doses of niacin-induced cholesterol efflux was positive correlation with LXRalpha and PPARgamma mRNA expression (r=0.83 P<0.01; r=0.76 P<0.05; respectively). CONCLUSION: Niacin can up-regulate LXRalpha and PPARgamma mRNA expression and promote the HDL-induced cholesterol efflux in adipocytes from hypercholesterolemic rabbits.

Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial.

CONTEXT: High-density lipoprotein (HDL) cholesterol is an inverse predictor of coronary atherosclerotic disease. Preliminary data have suggested that HDL infusions can induce atherosclerosis regression. OBJECTIVE: To investigate the effects of reconstituted HDL on plaque burden as assessed by intravascular ultrasound (IVUS). DESIGN AND SETTING: A randomized placebo-controlled trial was conducted at 17 centers in Canada. Intravascular ultrasound was performed to assess coronary atheroma at baseline and 2 to 3 weeks after the last study infusion. PATIENTS: Between July 2005 and October 2006, 183 patients had a baseline IVUS examination and of those, 145 had evaluable serial IVUS examinations after 6 weeks. INTERVENTION: Sixty patients were randomly assigned to receive 4 weekly infusions of placebo (saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111); and 12 to receive 80 mg/kg of CSL-111. MAIN OUTCOME MEASURES: The primary efficacy parameter was the percentage change in atheroma volume. Nominal changes in plaque volume and plaque characterization index on IVUS and coronary score on quantitative coronary angiography were also prespecified end points. RESULTS: The higher-dosage CSL-111 treatment group was discontinued early because of liver function test abnormalities. The percentage change in atheroma volume was -3.4% with CSL-111 and -1.6% for placebo (P = .48 between groups, P<.001 vs baseline for CSL-111). The nominal change in plaque volume was -5.3 mm3 with CSL-111 and -2.3 mm3 with placebo (P = .39 between groups, P<.001 vs baseline for CSL-111). The mean changes in plaque characterization index on IVUS (-0.0097 for CSL-111 and 0.0128 with placebo) and mean changes in coronary score (-0.039 mm for CSL-111 and -0.071 mm with placebo) on quantitative coronary angiography were significantly different between groups (P = .01 and P =.03, respectively). Administration of CSL-111 40 mg/kg was associated with mild, self-limiting transaminase elevation but was clinically well tolerated. CONCLUSIONS: Short-term infusions of reconstituted HDL resulted in no significant reductions in percentage change in atheroma volume or nominal change in plaque volume compared with placebo but did result in statistically significant improvement in the plaque characterization index and coronary score on quantitative coronary angiography. Elevation of HDL remains a valid target in vascular disease and further studies of HDL infusions, including trials with clinical end points, appear warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00225719

Nonpharmacologic approaches for the treatment of hyperlipidemia.

Coronary heart disease (CHD) is the leading cause of death in the United States. Dyslipidemias, like decreased high-density lipoprotein (HDL) and increased low-density lipoprotein (LDL), have been linked through epidemiologic and experimental studies with the development of atherosclerosis and an increased risk of CHD. The introduction of various classes of lipid-lowering drugs, especially the hydroxymethylglutaryl-coenzyme-A-reductase inhibitors (statins), has allowed for effective treatment of hyperlipidemia. This article reviews the following nonpharmacologic approaches to hyperlipidemia: LDL apheresis, surgery, the emergence of HDL as a therapeutic target, gene therapy, and finally, the possibility of developing a vaccine against atherosclerosis.