Niacin increases human aortic endothelial Sirt1 activity and nitric oxide: effect on endothelial function and vascular aging.

OBJECTIVES: Vascular endothelium, the innermost monolayer of endothelial cells lining the vessel wall, plays a vital physiologic role in the functional integrity of the aorta. Endothelial-derived nitric oxide (NO) is an important molecule regulating vascular endothelial function by its vasodilatory properties and inhibiting pathological inflammatory and oxidative consequences of vascular aging and cardiovascular disorders. Sirtuin 1 (Sirt1), has recently emerged as an important regulator of vascular endothelial NO production. The effect of niacin on Sirt1 in human arterial tissue has not been studied. METHODS: Using primary cultures of human aortic endothelial cells (HAEC), we examined the effect of niacin on endothelial Nicotinamide Adenine Dinucleotide+ (NAD+), Sirt1 and NO production. RESULTS: In HAEC, we show that pharmacologically relevant doses of niacin at 0.2-0.3 mM for 24 h significantly increased cellular NAD+ levels, Sirt1 activity, and NO production as compared to controls. Using silencing of Sirt1 by siRNA, we observed that Sirt1 mediates niacin-induced NO production. CONCLUSIONS: Translationally, these findings suggest that Sirt1 activation by niacin may be one of the mechanisms of action of niacin acting on NO to improve endothelial function and mitigate human vascular aging and its deleterious cardiovascular consequences.

Niacin regresses collagen content in human hepatic stellate cells from liver transplant donors with fibrotic non-alcoholic steatohepatitis (NASH).

In patients with non-alcoholic steatohepatitis (NASH), the onset of fibrosis is a major predictor of cirrhosis and its deadly complications. There is no approved effective pharmacologic therapy for liver fibrosis. Niacin (in pharmacologic concentrations or dose) reverses hepatic steatosis and steatohepatitis. Niacin's efficacy on human hepatic fibrosis is unknown. We investigated the effect of niacin on reversal of preexisting collagen content, in cultured primary human hepatic stellate cells (HSC) obtained from 7 donor livers (processed for transplantation) selected from 5 deceased patients having histologically diagnosed NASH with fibrosis (F1-F3) and 2 non-NASH-fibrosis subjects (Samsara Sciences, Inc., now LifeNet Health). Pharmacologically relevant concentrations of niacin produced a robust and significant dose and time-dependent regression of pre-existing fibrosis by an average of 47.6% and 60.1% (0.25 and 0.5 mM niacin at 48 h incubation) and 53.5% and 65.0% (0.25 and 0.5 mM niacin at 96 h incubation), respectively. In stellate cells from non-NASH-fibrosis subjects, niacin prevented, and regressed fibrosis induced by liver fibrosis stimulators, transforming growth factor-ß (TGF-ß) and hydrogen peroxide. Niacin significantly inhibited oxidative stress induced by stressors, palmitic acid, or hydrogen peroxide by 52% and 50%, respectively. Translationally, these human HSC data, coupled with emerging in vivo animal data and in vitro human hepatocyte data, suggest that niacin (used clinically for dyslipidemia) could be repurposed as an effective drug for the clinical treatment of patients with NASH-fibrosis or liver cirrhosis. This is in addition to its known efficacy for reversing steatohepatitis and steatosis which can also result in liver cirrhosis.

Testosterone concentrations and risk of cardiovascular events in androgen-deficient men with atherosclerotic cardiovascular disease.

BACKGROUND: Whether androgen deficiency among men increases the risk of cardiovascular (CV) events or is merely a disease marker remains a subject of intense scientific interest. OBJECTIVES: Among male subjects in the AIM-HIGH Trial with metabolic syndrome and low baseline levels of high-density lipoprotein (HDL)-cholesterol who were randomized to niacin or placebo plus simvastatin, we examined the relationship between low baseline testosterone (T) concentrations and subsequent CV outcomes during a mean 3-year follow-up. METHODS: In this post hoc analysis of men with available baseline plasma T concentrations, we examined the relationship between clinical/demographic characteristics and T concentrations both as a continuous and dichotomous variable (<300 ng/dL ["low T"] vs. ≥300 ng/dL ["normal T"]) on rates of pre-specified CV outcomes, using Cox proportional hazards models. RESULTS: Among 2118 male participants in whom T concentrations were measured, 643 (30%) had low T and 1475 had normal T concentrations at baseline. The low T group had higher rates of diabetes mellitus, hypertension, elevated body mass index, metabolic syndrome, higher blood glucose, hemoglobin A1c, and triglyceride levels, but lower levels of both low-density lipoprotein and HDL-cholesterol, and a lower rate of prior myocardial infarction (MI). Men with low T had a higher risk of the primary composite outcome of coronary heart disease (CHD) death, MI, stroke, hospitalization for acute coronary syndrome, or coronary or cerebral revascularization (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07, and a higher risk of the CHD death, MI, and stroke composite endpoint (11.8% vs. 8.2%; final adjusted HR 1.37, P = .04), respectively. CONCLUSIONS: In this post hoc analysis, there was an association between low baseline testosterone concentrations and increased risk of subsequent CV events in androgen-deficient men with established CV disease and metabolic syndrome, particularly for the composite secondary endpoint of CHD death, MI, and stroke. CONDENSED ABSTRACT: In this AIM-HIGH Trial post hoc analysis of 2118 men with metabolic syndrome and low HDL-cholesterol with available baseline plasma testosterone (T) samples, 643 males (30%) had low T (mean: 229 ng/dL) and 1475 (70%) had normal T (mean: 444 ng/dL) concentrations. The "low T" group had a 24% higher risk of the primary 5-component endpoint (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07). There was also a 31% higher risk of the secondary composite endpoint: coronary heart disease death, myocardial infarction, and stroke (11.8% vs. 8.2%, final adjusted HR 1.37, P = .04) in the low vs. normal T group, respectively.

Niacin for treatment of nonalcoholic fatty liver disease (NAFLD): novel use for an old drug?

Niacin has been widely used clinically for over half a century for dyslipidemia. Recent new evidence indicates that niacin may be useful in the treatment of nonalcoholic fatty liver disease (NAFLD) and its sequential complications including nonalcoholic steatohepatitis and fibrosis. There is an urgent unmet need for a cost-effective solution for this public health problem affecting nearly one in three adults. Niacin inhibits and reverses hepatic steatosis and inflammation in animals and liver cell cultures. It prevents liver fibrosis in animals and decreases collagen in cultured human stellate cells. Its mechanism of action is by oxidative stress reduction and inhibition of diacylglycerol acyltransferase 2 and other possible targets. An uncontrolled clinical trial in 39 hypertriglyceridemic patients with steatosis showed reduction of liver fat by 47% and reductions in liver enzymes and C-reactive protein from the baseline when treated with niacin extended-release for 6 months These hypothesis-generating data indicate a novel repurposed use of niacin for NAFLD. Niacin beneficially affects NAFLD at 3 major stages directly and, by affecting steatosis, it indirectly decreases the cascade effect on inflammation and fibrosis. It offers the advantage potentially of combination with other drugs in development for evolving synergistically more intense and broader efficacy. In select patients, it may benefit frequently associated atherogenic dyslipidemia. A randomized placebo-controlled double-blind parallel trial (with niacin alone or in combination with another drug in development) to assess the safety and efficacy of niacin on steatosis, inflammation, and fibrosis in patients with nonalcoholic steatohepatitis/NAFLD is warranted.

Serum Endocannabinoid Levels in Patients With End-Stage Renal Disease.

CONTEXT: Previous studies have shown that the endocannabinoid system plays a major role in energy metabolism through the actions of its main mediators, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide (AEA). OBJECTIVE: We examined serum levels of major endocannabinoid mediators and their association with clinical parameters in patients with end-stage renal disease (ESRD). DESIGN AND SETTING: Serum concentrations of 2-AG and AEA were measured in patients on maintenance hemodialysis (MHD) and controls, and correlations with various clinical and laboratory indices were examined. 2-AG was also measured in age and sex-matched healthy subjects for comparison of levels in patients undergoing MHD. MAIN OUTCOME MEASURE: Serum 2-AG. RESULTS: Serum 2-AG levels were significantly elevated in patients with ESRD compared with healthy controls. Higher levels of 2-AG were found in patients on MHD compared to healthy subjects, and similar findings were seen in a second set of subjects in independent analyses. Among 96 patients on MHD, 2-AG levels correlated significantly and positively with serum triglycerides (ρ = 0.43; P < 0.0001), body mass index (ρ = 0.40; P < 0.0001), and body anthropometric measures and negatively with serum high-density lipoprotein cholesterol (ρ = -0.33; P = 0.001) following adjustment for demographic and clinical variables. CONCLUSIONS: In patients on MHD, levels of serum 2-AG, a major endocannabinoid mediator, were increased. In addition, increasing serum 2-AG levels correlated with increased serum triglycerides and markers of body mass. Future studies will need to evaluate the potential mechanisms responsible for these findings.

Effects of Extended-Release Niacin on Quartile Lp-PLA2 Levels and Clinical Outcomes in Statin-treated Patients with Established Cardiovascular Disease and Low Baseline Levels of HDL-Cholesterol: Post Hoc Analysis of the AIM HIGH Trial.

BACKGROUND: Lipoprotein-associated phospholipase A2 (LpPLA2) is an inflammatory marker that has been associated with the presence of vulnerable plaque and increased risk of cardiovascular (CV) events. OBJECTIVE: To assess the effect of extended-release niacin (ERN) on Lp-PLA2 activity and clinical outcomes. METHODS: We performed a post hoc analysis in 3196 AIM-HIGH patients with established CV disease and low baseline levels of high-density lipoprotein cholesterol (HDL-C) who were randomized to ERN versus placebo on a background of simvastatin therapy (with or without ezetimibe) to assess the association between baseline Lp-PLA2 activity and the rate of the composite primary end point (CV death, myocardial infarction, stroke, hospitalization for unstable angina, and symptom-driven revascularization). RESULTS: Participants randomized to ERN, but not those randomized to placebo, experienced a significant 8.9% decrease in LpPLA2. In univariate analysis, the highest quartile of LpPLA2 activity (>208 nmol/min/mL, Q4) was associated with higher event rates compared to the lower quartiles in the placebo group (log rank P = .032), but not in the ERN treated participants (log rank P = .718). However, in multivariate analysis, adjusting for sex, diabetes, baseline LDL-C, HDL-C, and triglycerides, there was no significant difference in outcomes between the highest Lp-PLA2 activity quartile versus the lower quartiles in both the placebo and the ERN groups. CONCLUSION: Among participants with stable CV disease on optimal medical therapy, elevated Lp-PLA2 was associated with higher CV events; however, addition of ERN mitigates this effect. This association in the placebo group was attenuated after multivariable adjustment, which suggests that Lp-PLA2 does not improve risk assessment beyond traditional risk factors.

Association of Serum Paraoxonase/Arylesterase Activity With All-Cause Mortality in Maintenance Hemodialysis Patients.

CONTEXT: In end-stage renal disease (ESRD), serum high-density lipoprotein cholesterol (HDL-C) level is not an accurate predictor of mortality, partly because it does not necessarily correlate with indices of HDL function. Paraoxonase (PON) is a major enzyme constituent of HDL and a key component of HDL antioxidant activity. Apolipoprotein A-I (Apo A-1) is the core HDL structural protein that plays a major role in various aspects of HDL function. OBJECTIVE: We sought to examine PON activity and Apo A-I levels in patients with ESRD vs healthy controls. DESIGN AND SETTING: PON/arylesterase activity was measured in 499 patients with maintenance hemodialysis (MHD) and 24 healthy controls with similar distributions of age, sex, and race/ethnicity. Serum acrolein-modified Apo A-I was measured in 30 patients with MHD and 10 healthy controls. MAIN OUTCOME MEASURES: Multilevel Cox models were used to assess associations among PON activity, Apo A-I, and HDL-C levels with 12-month all-cause mortality. RESULTS: PON activity was significantly lower in patients with MHD vs controls. Furthermore, acrolein-modified Apo A-I levels were higher in patients with MHD vs controls. In fully adjusted models, high PON activity was associated with lower 12-month mortality, whereas no difference of mortality risk was observed across HDL-C levels. The combination of high PON and low Apo A-I compared with low PON and low Apo A-I was associated with lower mortality risk. CONCLUSIONS: In patients with MHD, PON activity had a stronger association with 12-month mortality than HDL-C. Future studies are needed to examine the role of these markers as potential diagnostic and therapeutic tools in ESRD.

Statin Therapy Before Transition to End-Stage Renal Disease With Posttransition Outcomes.

Background Although studies have shown that statin therapy in patients with non-dialysis-dependent chronic kidney disease was associated with a lower risk of death, this was not observed in dialysis patients newly initiated on statins. It is unclear if statin therapy benefits administered during the predialysis period persist after transitioning to end-stage renal disease. Methods and Results In 47 720 veterans who transitioned to end-stage renal disease during 2007 to 2014, we examined the association of statin therapy use 1 year before transition with posttransition all-cause and cardiovascular mortality and hospitalization incidence rates over the first 12 months of follow-up. Associations were examined using multivariable adjusted Cox proportional hazard models and negative binomial regressions. Sensitivity analyses included propensity score and subgroup analyses. The cohort's mean± SD age was 71±11 years, and the cohort included 4% women, 23% blacks, and 66% diabetics. Over 12 months of follow-up, there were 13 411 deaths, with an incidence rate of 35.3 (95% CI , 34.7-35.8) deaths per 100 person-years. In adjusted models, statin therapy compared with no statin therapy was associated with lower risks of 12-month all-cause (hazard ratio [95% CI], 0.79 [0.76-0.82]) and cardiovascular (hazard ratio [95% CI ], 0.83 [0.78-0.88]) mortality, as well as with a lower rate of hospitalizations (incidence rate ratio [95% CI ], 0.89 [0.87-0.92]) after initiating dialysis. These lower outcome risks persisted across strata of clinical characteristics, and in propensity score analyses. Conclusions Among veterans with non-dialysis-dependent chronic kidney disease, treatment with statin therapy within the 1 year before transitioning to end-stage renal disease is associated with favorable early end-stage renal disease outcomes.

Cardiovascular outcomes during extended follow-up of the AIM-HIGH trial cohort.

BACKGROUND: Epidemiologic studies have shown that low levels of high-density lipoprotein-cholesterol (HDL-C) and elevated triglycerides are independent predictors of cardiovascular (CV) events, though randomized trials of HDL-C-raising therapies to reduce clinical events have been largely disappointing. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial failed to show that extended release niacin (ERN) reduced CV events in patients with atherogenic dyslipidemia who were on statin-based therapy. OBJECTIVE: We sought to determine whether extended follow-up of AIM-HIGH participants changed these null results. METHODS: AIM-HIGH was a placebo-controlled trial of 3414 patients with established CV disease, low baseline HDL-C, and elevated triglycerides levels randomized to ERN 1500-2000 mg/d vs placebo. Participants also received simvastatin with or without ezetimibe to attain on-treatment low-density lipoprotein cholesterol levels of 40-80 mg/dL. The trial was halted after a mean 3-year follow-up because of futility. RESULTS: Among 3236 participants alive at the end of blinded study, 2613 (81%; ERN = 1,312, placebo = 1301) were followed a mean 1.1 additional years. Ninety-five percent of subjects remained on statin, but only 4% on ERN. At a mean total follow-up of 4.1 years, there were 343 primary CV endpoints in the ERN arm and 305 CV endpoints in placebo participants (HR 1.11, 95% CI 0.96, 1.30). Ischemic stroke was also not significantly different after extended follow-up in the two groups (2.2% vs 1.5%, P = .13). CONCLUSIONS: In patients with CV disease and atherogenic dyslipidemia on statin-based therapy, 3 years of ERN treatment did not lower CV event rates. An additional year of follow-up off assigned treatment did not alter these findings.

Inverse Association Between Serum Non-High-Density Lipoprotein Cholesterol Levels and Mortality in Patients Undergoing Incident Hemodialysis.

BACKGROUND: There is accumulating evidence that serum levels of non-high-density lipoprotein cholesterol (non-HDL-C) are a more accurate predictor of cardiovascular outcomes when compared with low-density lipoprotein cholesterol. However, we recently found that higher serum concentrations of triglycerides are associated with better outcomes in patients undergoing hemodialysis. Therefore, we hypothesized that the association of serum levels of non-HDL-C (which includes triglyceride-rich lipoproteins) with outcomes may also be different in patients undergoing hemodialysis when compared with other patient populations. METHODS AND RESULTS: We studied the association of baseline and time-dependent serum levels of non-HDL-C with all-cause and cardiovascular mortality using Cox proportional hazard regression models in a nationally representative cohort of 50 118 patients undergoing incident hemodialysis from January 1, 2007, to December 31, 2011. In time-dependent models adjusted for case mix and surrogates of malnutrition and inflammation, a graded inverse association between non-HDL-C level and mortality was demonstrated with hazard ratios (95% confidence intervals) of the lowest (<60 mg/dL) and highest (≥160 mg/dL) categories: 1.88 (1.72-2.06) and 0.73 (0.64-0.83) for all-cause mortality and 2.07 (1.78-2.41) and 0.75 (0.60-0.93) for cardiovascular mortality, respectively (reference, 100-115 mg/dL). In analyses using baseline values, non-HDL-C levels <100 mg/dL were also associated with significantly higher mortality risk across all levels of adjustment. Similar associations were found when evaluating non-HDL/HDL cholesterol ratio and mortality, with the highest all-cause and cardiovascular mortality being observed in patients with decreased non-HDL/HDL-C ratio (<2.5). CONCLUSIONS: Contrary to the general population, decrements in non-HDL-C and non-HDL/HDL cholesterol ratio were paradoxically associated with increased all-cause and cardiovascular mortality in patients undergoing incident hemodialysis. The underlying mechanisms responsible for these associations await further investigation.

Increments in serum high-density lipoprotein cholesterol over time are not associated with improved outcomes in incident hemodialysis patients.

BACKGROUND: Elevated serum high-density lipoprotein cholesterol (HDL-C) has not been associated with better cardiovascular (CV) and all-cause mortality in hemodialysis patients. However, the association between change in HDL over time and mortality has not been fully examined. OBJECTIVE: In a nationally representative cohort of incident hemodialysis patients who had available HDL data at baseline and 6 months after dialysis initiation, we studied the association of change in HDL-C during the first 6 months of dialysis with all-cause and CV mortality. METHODS: Associations between HDL-C change and mortality were determined in Cox proportional hazard regression models with adjustment for multiple variables. RESULTS: In case-mix models, there was a J-shaped association between change in HDL-C and mortality, such that quartiles 1 (<-5 mg/dL) and 4 (≥7 mg/dL) were each associated with higher all-cause (hazard ratio, 1.32 [95% confidence interval, 1.21-1.45] and 1.09 [1.01-1.18]) and CV (1.28 [1.06-1.55] and 1.23 [1.04-1.45]) death risk, respectively. In fully adjusted models that included indices of malnutrition and inflammation, the higher death risk observed in the lowest quartile was attenuated, whereas the highest quartile continued to demonstrate significantly higher all-cause (1.11 [1.02-1.20]) and CV mortality (1.15 [1.00-1.32]). These associations persisted across various subgroups. CONCLUSIONS: Although malnutrition and inflammation may explain the increased risk for mortality in patients with decreasing serum HDL-C concentrations over time, these indices do not mitigate the elevated risk in patients with rising serum HDL-C. We found that increasing serum HDL-C over time is paradoxically associated with worse outcomes in incident hemodialysis patients.

LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with cardiac hypertrophy, fibrosis, and increased risk of cardiovascular mortality. LCZ696 (sacubitril/valsartan) is a promising agent that has shown significant potential in treatment of heart failure. We hypothesized that LCZ696 is more effective than valsartan alone in the treatment of cardiovascular abnormalities associated with experimental CKD. METHODS AND RESULTS: Male Sprague-Dawley rats underwent 5/6 nephrectomy and were subsequently randomized to no treatment (CKD), 30 mg/kg valsartan (VAL), or 60 mg/kg LCZ696 (LCZ). After 8 weeks, cardiovascular parameters, including markers of inflammation, oxidative stress, mitochondrial abundance/function, hypertrophy, and fibrosis, were measured. Treatment with LCZ resulted in significant improvements in the heart-body weight ratio and serum concentrations of N-terminal pro-B-type natriuretic peptide and fibroblast growth factor 23 along with improvement of kidney function. In addition, LCZ ameliorated aortic fibrosis and cardiac hypertrophy and fibrosis, reduced markers of cardiac oxidative stress and inflammation, and improved indicators of mitochondrial mass/function. Although VAL also improved some of these indices, treatment with LCZ was more effective than VAL alone. CONCLUSIONS: CKD-associated cardiovascular abnormalities, including myocardial hypertrophy, fibrosis, inflammation, oxidative stress, and mitochondrial depletion/dysfunction, were more effectively attenuated by LCZ treatment than by VAL alone.

Association of Serum Triglyceride to HDL Cholesterol Ratio with All-Cause and Cardiovascular Mortality in Incident Hemodialysis Patients.

BACKGROUND AND OBJECTIVES: Elevated serum triglyceride/HDL cholesterol (TG/HDL-C) ratio has been identified as a risk factor for cardiovascular (CV) disease and mortality in the general population. However, the association of this important clinical index with mortality has not been fully evaluated in patients with ESRD on maintenance hemodialysis (MHD). We hypothesized that the association of serum TG/HDL-C ratio with all-cause and CV mortality in patients with ESRD on MHD is different from the general population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied the association of serum TG/HDL-C ratio with all-cause and CV mortality in a nationally representative cohort of 50,673 patients on incident hemodialysis between January 1, 2007 and December 31, 2011. Association of baseline and time-varying TG/HDL-C ratios with mortality was assessed using Cox proportional hazard regression models, with adjustment for multiple variables, including statin therapy. RESULTS: During the median follow-up of 19 months (interquartile range, 11-32 months), 12,778 all-cause deaths and 4541 CV deaths occurred, respectively. We found that the 10th decile group (reference: sixth deciles of TG/HDL-C ratios) had significantly lower risk of all-cause mortality (hazard ratio, 0.91 [95% confidence interval, 0.83 to 0.99] in baseline and 0.86 [95% confidence interval, 0.79 to 0.94] in time-varying models) and CV mortality (hazard ratio, 0.83 [95% confidence interval, 0.72 to 0.96] in baseline and 0.77 [95% confidence interval, 0.66 to 0.90] in time-varying models). These associations remained consistent and significant across various subgroups. CONCLUSIONS: Contrary to the general population, elevated TG/HDL-C ratio was associated with better CV and overall survival in patients on hemodialysis. Our findings provide further support that the nature of CV disease and mortality in patients with ESRD is unique and distinct from other patient populations. Hence, it is vital that future studies focus on identifying risk factors unique to patients on MHD and decipher the underlying mechanisms responsible for poor outcomes in patients with ESRD.

Reverse Epidemiology of Traditional Cardiovascular Risk Factors in the Geriatric Population.

Traditional risk factors of cardiovascular death in the general population, including body mass index (BMI), serum cholesterol, and blood pressure (BP), are also found to relate to outcomes in the geriatric population, but in an opposite direction. Some degrees of elevated BMI, serum cholesterols, and BP are reportedly associated with lower, instead of higher, risk of death among the elderly. This phenomenon is termed "reverse epidemiology" or "risk factor paradox" (such as obesity paradox) and is also observed in a variety of chronic disease states such as end-stage renal disease requiring dialysis, chronic heart failure, rheumatoid arthritis, and AIDS. Several possible causes are hypothesized to explain this risk factor reversal: competing short-term and long-term killers, improved hemodynamic stability in the obese, adipokine protection against tumor necrosis factor-α, lipoprotein protection against endotoxins, and lipophilic toxin sequestration by the adipose tissue. It is possible that the current thresholds for intervention and goal levels for such traditional risk factors as BMI, serum cholesterol, and BP derived based on younger populations do not apply to the elderly, and that new levels for such risk factors should be developed for the elderly population. Reverse epidemiology of conventional cardiovascular risk factors may have a bearing on the management of the geriatric population, thus it deserves further attention.

Association of serum lipids with outcomes in Hispanic hemodialysis patients of the West versus East Coasts of the United States.

BACKGROUND: Paradoxical associations exist between serum lipid levels and mortality in patients on maintenance hemodialysis (MHD) including those of Hispanic origin. However, there are significant racial and ethnic variations in patients of 'Hispanic' background. We hypothesized that clinically meaningful differences existed in the association between lipids and survival in Hispanic MHD patients on the West versus East Coast. METHODS: We examined the survival impact of serum lipids in a 2-year cohort of 15,109 MHD patients of Hispanic origin being treated in California, Texas, representing the West versus New York, New Jersey and Florida representing the East Coast, using Cox models with various degrees of adjustments. RESULTS: The association of serum total and HDL cholesterol with mortality follows a U-shaped pattern in Hispanic patients residing in the West. This is in contrast to Hispanic patients in the East Coast whose survival seems to improve with increasing total and HDL cholesterol levels. Elevated serum LDL levels in Hispanic patients on the West Coast are associated with a significant increase in mortality, while this association is not observed in patients residing on the East Coast. CONCLUSIONS: Substantial differences exist in the association of serum lipids with mortality in MHD patients of Hispanic background depending on whether they reside on the West or East Coast of the United States. These geographical variances most likely reflect ethnic, racial and genetic distinctions, which are usually ignored. Future studies should take into account these critical variations in a population of patients who make up a significant portion of our society.

Niacin inhibits fat accumulation, oxidative stress, and inflammatory cytokine IL-8 in cultured hepatocytes: Impact on non-alcoholic fatty liver disease.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a common disorder characterized by excessive hepatic fat accumulation, production of reactive oxygen species (ROS), inflammation and potentially resulting in non-alcoholic steatohepatitis (NASH), cirrhosis and end-stage liver disease. Recently, we have shown that niacin significantly prevented hepatic steatosis and regressed pre-existing steatosis in high-fat fed rat model of NAFLD. To gain further insight into the cellular mechanisms, this study investigated the effect of niacin on human hepatocyte fat accumulation, ROS production, and inflammatory mediator IL-8 secretion. MATERIALS AND METHODS: Human hepatoblastoma cell line HepG2 or human primary hepatocytes were first stimulated with palmitic acid followed by treatment with niacin or control for 24 h. RESULTS: The data indicated that niacin (at 0.25 and 0.5 mmol/L doses) significantly inhibited palmitic acid-induced fat accumulation in human hepatocytes by 45-62%. This effect was associated with inhibition of diacylglycerol acyltransferase 2 (DGAT2) mRNA expression without affecting the mRNA expression of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1). Niacin attenuated hepatocyte ROS production and it also inhibited NADPH oxidase activity. Niacin reduced palmitic acid-induced IL-8 levels. CONCLUSIONS: These findings suggest that niacin, through inhibiting hepatocyte DGAT2 and NADPH oxidase activity, attenuates hepatic fat accumulation and ROS production respectively. Decreased ROS production, at least in part, may have contributed to the inhibition of pro-inflammatory IL-8 levels. These mechanistic studies may be useful for the clinical development of niacin and niacin-related compounds for the treatment of NAFLD/NASH and its complications.

Niacin and progression of CKD.

Niacin is the oldest drug available for the treatment of dyslipidemia. It has been studied extensively and tested in clinical trials of atherosclerotic cardiovascular disease prevention and regression in the general population, but not specifically in patients with chronic kidney disease (CKD), who are at extremely high residual risk despite current therapy. Despite the current controversy about recent trials with niacin, including their limitations, there may be a place for this agent in select patients with CKD with dyslipidemia. Niacin has a favorable unique impact on factors affecting the rate of glomerular filtration rate decline, including high-density lipoprotein (HDL) particle number and function, triglyceride levels, oxidant stress, inflammation and endothelial function, and lowering of serum phosphorus levels by reducing dietary phosphorus absorption in the gastrointestinal tract. These effects may slow glomerular filtration rate decline and ultimately improve CKD outcomes and prevent cardiovascular risk. This review presents the clinically relevant concept that niacin holds significant potential as a renoprotective therapeutic agent. In addition, this review concludes that clinical investigations to assess the effect of niacin (in addition to aggressive low-density lipoprotein cholesterol lowering) on reduction of cardiovascular events in patients with CKD with very low HDL cholesterol (or those with identified dysfunctional HDL) and elevated triglyceride levels need to be considered seriously to address the high residual risk in this population.

Niacin decreases leukocyte myeloperoxidase: mechanistic role of redox agents and Src/p38MAP kinase.

OBJECTIVES: Leukocyte myeloperoxidase (MPO) is a major player in the pathogenesis of various chronic diseases including atherosclerosis. This study proposes the novel concept that niacin, through reactive oxygen species (ROS)-mediated signaling, decreases neutrophil MPO release and its activity, protects apolipoprotein-AI (apo-AI) modification and improves HDL function. METHODS: Human blood leukocytes and leukocytic cell line HL-60 cells were treated with niacin, and stimulated with phorbol myristate acetate (PMA). Cellular and released MPO activity in the medium was measured by assessing chlorination of MPO-specific substrate. MPO protein release in the medium and apo-AI degradation was measured by Western blot analysis. Monocyte adhesion to human aortic primary endothelial cells was measured to assess biological function of HDL/apo-AI. RESULTS: PMA significantly increased leukocyte MPO activity in both intracellular extract and medium. Niacin (0.25-0.5 mM) decreased PMA-induced MPO activity (cellular and released in the media). Niacin also decreased MPO protein mass in the medium without affecting its mRNA expression. Increased NADPH oxidase and ROS production by PMA were also significantly inhibited by niacin. Studies with specific inhibitors suggest that ROS-dependent Src and p38MAP kinase mediate decreased MPO activity by niacin. Niacin blocked apo-AI degradation, and apo-AI from niacin treated cells decreased monocyte adhesion to aortic endothelial cells. CONCLUSIONS: These findings identify niacin as a potent inhibitor of leukocyte MPO release and MPO-mediated formation of dysfunctional HDL. Niacin and niacin-related chemical entities may form important therapeutic agents for MPO-mediated inflammatory diseases.

Elevated high-density lipoprotein cholesterol and cardiovascular mortality in maintenance hemodialysis patients.

BACKGROUND: High-density lipoprotein (HDL) confers protection against atherosclerosis by several different mechanisms. Although in the general population, increasing levels of HDL are associated with reduced cardiovascular (CV) mortality, this association is not well known in patients with chronic disease states such as end-stage renal disease. We hypothesize that the association of serum HDL concentration and its ratio to total cholesterol with all-cause and CV mortality in hemodialysis patients is different from the general population. METHODS: A 3-year (July 2004 to June 2007) cohort of 33 109 chronic hemodialysis patients was studied in the USA in the dialysis clinics where lipid profile was measured in at least 50% of all outpatients of the clinic during a given calendar quarter. Cox proportional hazard models were adjusted for demographics and case-mix variables and cubic splines were plotted. RESULTS: Higher HDL concentrations up to 50 mg/dL were associated with better overall survival, while HDL at 60 mg/dL and above was associated with a rise in all-cause and CV mortality. All-cause and CV mortality hazard ratio was 1.28 (1.20-1.38) and 1.08 (1.01-1.16) for HDL <30 mg/dL and 1.05 (1.00-1.10) and 1.08 (1.00-1.16) for HDL ≥ 60 mg/dL, respectively (reference: HDL: 30-<60 mg/dL). CONCLUSIONS: In contrast to the general population, low total cholesterol to HDL ratio was associated with higher mortality in hemodialysis patients. A U-shaped association between HDL cholesterol level and all-cause and CV mortality exists in hemodialysis patients with HDL between 50 and <60 mg/dL exhibiting the best survival. The underlying mechanisms responsible for these seemingly paradoxical associations await further investigation.