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1.
Am J Transl Res ; 15(12): 6771-6778, 2023.
Article in English | MEDLINE | ID: mdl-38186996

ABSTRACT

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.

2.
Am J Transl Res ; 14(6): 4006-4014, 2022.
Article in English | MEDLINE | ID: mdl-35836902

ABSTRACT

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.

3.
J Clin Lipidol ; 13(6): 873-879, 2019.
Article in English | MEDLINE | ID: mdl-31706905

ABSTRACT

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.


Subject(s)
Hypolipidemic Agents/therapeutic use , Niacin/therapeutic use , Non-alcoholic Fatty Liver Disease/drug therapy , Animals , Double-Blind Method , Humans , Oxidative Stress/drug effects
4.
J Endocr Soc ; 3(10): 1869-1880, 2019 Oct 01.
Article in English | MEDLINE | ID: mdl-31583368

ABSTRACT

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.

5.
J Cardiovasc Pharmacol Ther ; 24(6): 534-541, 2019 11.
Article in English | MEDLINE | ID: mdl-31131629

ABSTRACT

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.


Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/blood , Cardiovascular Diseases/drug therapy , Cholesterol, HDL/blood , Dyslipidemias/drug therapy , Hypolipidemic Agents/therapeutic use , Niacin/therapeutic use , Aged , Biomarkers/blood , Cardiovascular Diseases/blood , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/mortality , Delayed-Action Preparations , Dyslipidemias/blood , Dyslipidemias/diagnosis , Dyslipidemias/mortality , Ezetimibe/therapeutic use , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypolipidemic Agents/adverse effects , Male , Middle Aged , Niacin/adverse effects , Risk Assessment , Risk Factors , Simvastatin/therapeutic use , Time Factors , Treatment Outcome
6.
J Am Heart Assoc ; 8(6): e011869, 2019 03 19.
Article in English | MEDLINE | ID: mdl-30885048

ABSTRACT

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.


Subject(s)
Cardiovascular Diseases/prevention & control , Hospitalization/trends , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Kidney Failure, Chronic/drug therapy , Propensity Score , Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Female , Follow-Up Studies , Humans , Incidence , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/mortality , Male , Retrospective Studies , Survival Rate/trends , Treatment Outcome , United States/epidemiology
7.
J Clin Endocrinol Metab ; 104(10): 4848-4856, 2019 10 01.
Article in English | MEDLINE | ID: mdl-30920627

ABSTRACT

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.


Subject(s)
Aryldialkylphosphatase/blood , Carboxylic Ester Hydrolases/blood , Kidney Failure, Chronic , Renal Dialysis , Adult , Aged , Apolipoprotein A-I/blood , Biomarkers/blood , Case-Control Studies , Cause of Death , Cholesterol, HDL/blood , Cohort Studies , Female , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/therapy , Male , Middle Aged , Renal Dialysis/mortality , Survival Analysis
8.
J Am Heart Assoc ; 7(12)2018 06 09.
Article in English | MEDLINE | ID: mdl-29886420

ABSTRACT

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.


Subject(s)
Cholesterol/blood , Dyslipidemias/blood , Kidney Failure, Chronic/therapy , Renal Dialysis , Aged , Biomarkers/blood , Cause of Death , Dyslipidemias/diagnosis , Dyslipidemias/mortality , Female , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/mortality , Male , Middle Aged , Prognosis , Renal Dialysis/adverse effects , Renal Dialysis/mortality , Risk Assessment , Risk Factors , Time Factors
9.
J Clin Lipidol ; 12(2): 488-497, 2018.
Article in English | MEDLINE | ID: mdl-29456130

ABSTRACT

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.


Subject(s)
Cardiovascular Diseases/blood , Cholesterol, HDL/blood , Outcome Assessment, Health Care/statistics & numerical data , Renal Dialysis/statistics & numerical data , Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/mortality , Cause of Death , Cohort Studies , Female , Humans , Incidence , Male , Middle Aged , Outcome Assessment, Health Care/methods , Proportional Hazards Models , Renal Dialysis/mortality , Time Factors
10.
J Card Fail ; 24(4): 266-275, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29325796

ABSTRACT

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.


Subject(s)
Aminobutyrates , Cardiomegaly , Heart Failure , Stroke Volume , Tetrazoles , Animals , Male , Rats , Aminobutyrates/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Biphenyl Compounds , Cardiomegaly/complications , Cardiomegaly/drug therapy , Cardiomegaly/physiopathology , Disease Models, Animal , Drug Combinations , Fibrosis/complications , Fibrosis/drug therapy , Heart Failure/etiology , Heart Failure/physiopathology , Heart Failure/prevention & control , Neprilysin/antagonists & inhibitors , Random Allocation , Rats, Sprague-Dawley , Stroke Volume/drug effects , Stroke Volume/physiology , Tetrazoles/therapeutic use , Valsartan
11.
Clin J Am Soc Nephrol ; 12(4): 591-602, 2017 Apr 03.
Article in English | MEDLINE | ID: mdl-28193609

ABSTRACT

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.


Subject(s)
Cardiovascular Diseases/mortality , Cause of Death , Cholesterol, HDL/blood , Kidney Failure, Chronic/blood , Triglycerides/blood , Aged , Female , Follow-Up Studies , Humans , Kidney Failure, Chronic/therapy , Male , Middle Aged , Proportional Hazards Models , Renal Dialysis , Republic of Korea/epidemiology , Survival Rate
12.
Am J Nephrol ; 41(4-5): 284-95, 2015.
Article in English | MEDLINE | ID: mdl-26044456

ABSTRACT

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.


Subject(s)
Cholesterol, HDL/blood , Cholesterol, LDL/blood , Dyslipidemias/ethnology , Hispanic or Latino/statistics & numerical data , Kidney Failure, Chronic/therapy , Mortality/ethnology , Triglycerides/blood , Adult , Aged , California , Cohort Studies , Female , Florida , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/ethnology , Male , Middle Aged , New Jersey , New York , Proportional Hazards Models , Renal Dialysis , Retrospective Studies , Texas , United States
13.
Metabolism ; 64(9): 982-90, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26024755

ABSTRACT

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.


Subject(s)
Hypolipidemic Agents/pharmacology , Interleukin-8/metabolism , Lipid Metabolism/drug effects , Niacin/pharmacology , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , Oxidative Stress/drug effects , Diacylglycerol O-Acyltransferase/metabolism , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Palmitic Acid/pharmacology , Primary Cell Culture , Reactive Oxygen Species/metabolism
14.
Am J Kidney Dis ; 65(5): 785-98, 2015 May.
Article in English | MEDLINE | ID: mdl-25708553

ABSTRACT

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.


Subject(s)
Hypolipidemic Agents/therapeutic use , Niacin/therapeutic use , Renal Insufficiency, Chronic/prevention & control , Comorbidity , Coronary Artery Disease/epidemiology , Disease Progression , Endothelium, Vascular/drug effects , Humans , Hypolipidemic Agents/pharmacology , Niacin/pharmacology , Oxidative Stress/drug effects , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/physiopathology , Triglycerides/blood
16.
Atherosclerosis ; 235(2): 554-61, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24956528

ABSTRACT

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.


Subject(s)
Niacin/pharmacology , Peroxidase/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , src-Family Kinases/metabolism , Apolipoprotein A-I/metabolism , HL-60 Cells , Humans , Leukocytes/drug effects , Leukocytes/enzymology , NADPH Oxidases/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Tetradecanoylphorbol Acetate/pharmacology
17.
Nephrol Dial Transplant ; 29(8): 1554-62, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24574544

ABSTRACT

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.


Subject(s)
Cardiovascular Diseases/mortality , Cholesterol, HDL/blood , Kidney Failure, Chronic/therapy , Renal Dialysis , Biomarkers/blood , Cardiovascular Diseases/blood , Cardiovascular Diseases/etiology , Cause of Death/trends , Female , Follow-Up Studies , Humans , Incidence , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Male , Middle Aged , Prognosis , Proportional Hazards Models , Retrospective Studies , Survival Rate/trends , Time Factors , United States/epidemiology
18.
Am J Physiol Gastrointest Liver Physiol ; 306(4): G320-7, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-24356885

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver damage, comprises a spectrum of liver abnormalities including the early fat deposition in the liver (hepatic steatosis) and advanced nonalcoholic steatohepatitis. Niacin decreases plasma triglycerides, but its effect on hepatic steatosis is elusive. To examine the effect of niacin on steatosis, rats were fed either a rodent normal chow, chow containing high fat (HF), or HF containing 0.5% or 1.0% niacin in the diet for 4 wk. For regression studies, rats were first fed the HF diet for 6 wk to induce hepatic steatosis and were then treated with niacin (0.5% in the diet) while on the HF diet for 6 wk. The findings indicated that inclusion of niacin at 0.5% and 1.0% doses in the HF diet significantly decreased liver fat content, liver weight, hepatic oxidative products, and prevented hepatic steatosis. Niacin treatment to rats with preexisting hepatic steatosis induced by the HF diet significantly regressed steatosis. Niacin had no effect on the mRNA expression of fatty acid synthesis or oxidation genes (including sterol-regulatory element-binding protein 1, acetyl-CoA carboxylase 1, fatty acid synthase, and carnitine palmitoyltransferase 1) but significantly inhibited mRNA levels, protein expression, and activity of diacylglycerol acyltrasferase 2, a key enzyme in triglyceride synthesis. These novel findings suggest that niacin effectively prevents and causes the regression of experimental hepatic steatosis. Approved niacin formulation(s) for other indications or niacin analogs may offer a very cost-effective opportunity for the clinical development of niacin for treating NAFLD and fatty liver disease.


Subject(s)
Antioxidants/pharmacology , Fatty Liver/drug therapy , Fatty Liver/prevention & control , Lipid Metabolism/drug effects , Liver/drug effects , Niacin/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , Disease Models, Animal , Disease Progression , Fatty Acids, Nonesterified/metabolism , Fatty Liver/genetics , Fatty Liver/metabolism , Fatty Liver/pathology , Gene Expression Regulation, Enzymologic/drug effects , Inflammation Mediators/metabolism , Lipid Metabolism/genetics , Lipid Peroxidation/drug effects , Liver/metabolism , Liver/pathology , Male , Non-alcoholic Fatty Liver Disease , Oxidation-Reduction , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley , Thiobarbituric Acid Reactive Substances/metabolism , Time Factors , Triglycerides/metabolism , Tumor Necrosis Factor-alpha/metabolism
19.
J Am Coll Cardiol ; 62(17): 1575-9, 2013 Oct 22.
Article in English | MEDLINE | ID: mdl-23973688

ABSTRACT

OBJECTIVES: This study sought to examine the relationship between baseline and on-study apolipoproteins (apo) A-1 and B and lipoprotein(a) [Lp(a)] levels and the development of subsequent cardiovascular (CV) events in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) trial. BACKGROUND: Niacin has been reported to lower apoB and Lp(a) and to raise apoA-1. METHODS: Individuals with CV disease and low baseline levels of high-density lipoprotein cholesterol were randomized to simvastatin plus placebo or simvastatin, plus extended-release niacin ([ERN], 1,500 to 2,000 mg/day), with ezetimibe added as needed, in both groups, to maintain an on-treatment low-density lipoprotein cholesterol in the range of 40 to 80 mg/dl. Hazard ratios (HRs) were used to evaluate the relationship between levels of apoA-1, apoB, and Lp(a), and CV events in each treatment group. RESULTS: Baseline apoB and the apoB/apoA-I ratio were significantly predictive of CV events only for the placebo group (HR: 1.17 [p = 0.018] and HR: 1.19 [p = 0.016]). Baseline and on-study Lp(a) were predictive of CV events in both simvastatin plus placebo (baseline HR: 1.24 [p = 0.002] and on-study HR: 1.21 [p = 0.017]) and the simvastatin plus ERN group (baseline HR: 1.25 [p = 0.001] and on-study HR: 1.18 [p = 0.028]). The ERN modestly increased 1-year apoA-1 (7%), decreased apoB (13%), decreased the ApoB/ApoA-1 ratio (19%), and decreased Lp(a) 21%, but did not reduce CV events. CONCLUSIONS: Lp(a) was associated with increased CV risk in both treatment groups indicating that it contributes to residual CV risk. However, there was no evidence that ERN reduced CV risk, despite favorable lipoprotein changes.


Subject(s)
Apolipoprotein A-I/blood , Apolipoproteins B/blood , Cardiovascular Diseases/blood , Cholesterol, HDL/blood , Lipoprotein(a)/blood , Metabolic Syndrome/blood , Triglycerides/blood , Aged , Biomarkers/blood , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/epidemiology , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Hypertriglyceridemia/blood , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/epidemiology , Hypoalphalipoproteinemias/blood , Hypoalphalipoproteinemias/drug therapy , Hypoalphalipoproteinemias/epidemiology , Male , Metabolic Syndrome/drug therapy , Metabolic Syndrome/epidemiology , Middle Aged , Niacin/administration & dosage , Prospective Studies , Simvastatin/administration & dosage , Treatment Outcome
20.
J Am Coll Cardiol ; 62(17): 1580-4, 2013 Oct 22.
Article in English | MEDLINE | ID: mdl-23916935

ABSTRACT

OBJECTIVES: This study sought to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes in this secondary analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial. BACKGROUND: During a 3-year follow-up in 3,414 patients with established CV disease and low high-density lipoprotein cholesterol (HDL-C) levels, combined niacin + low-density lipoprotein cholesterol (LDL-C)-lowering therapy did not reduce CV events compared with LDL-C-lowering therapy alone. METHODS: Subjects taking simvastatin and/or ezetimibe were randomized to receive extended-release (ER) niacin 1,500 to 2,000 mg or minimal immediate-release niacin (≤ 150 mg) as placebo at bedtime. LDL-C levels in both groups were maintained from 40 to 80 mg/dl. Hazard ratios were estimated by using Cox proportional hazards models for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. RESULTS: CV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (≥ 198 mg/dl) and lowest HDL-C (<33 mg/dl) tertiles, ER niacin showed a trend toward benefit (hazard ratio: 0.74, p = 0.073). In-trial LDL-C levels, non-HDL-C levels, and the total cholesterol/HDL-C ratio were positively associated with CV events in the control group, but these relationships were absent in the ER niacin group. CONCLUSIONS: Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-C-lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could affect risk. (Niacin Plus Statin to Prevent Vascular Events [AIM-HIGH]; NCT00120289).


Subject(s)
Cardiovascular Diseases/blood , Cholesterol, HDL/blood , Global Health , Metabolic Syndrome/blood , Triglycerides/blood , Aged , Anticholesteremic Agents/administration & dosage , Biomarkers/blood , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/epidemiology , Double-Blind Method , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Lipoproteins/blood , Male , Metabolic Syndrome/drug therapy , Metabolic Syndrome/epidemiology , Middle Aged , Niacin/administration & dosage , Prospective Studies , Treatment Outcome
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