Hyperlipidemias: Eckel RH

Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, Hong Y, Eckel RH, Anonymous00031. · No affiliation provided · Circulation. · Pubmed #15509809 links to  free full text

Abstract: Obesity adversely affects cardiac function, increases the risk factors for coronary heart disease, and is an independent risk factor for cardiovascular disease. The risk of developing coronary heart disease is directly related to the concomitant burden of obesity-related risk factors. Modest weight loss can improve diastolic function and affect the entire cluster of coronary heart disease risk factors simultaneously. This statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism reviews the relationship between obesity and the cardiovascular system, evaluates the effect of weight loss on coronary heart disease risk factors and coronary heart disease, and provides practical weight management treatment guidelines for cardiovascular healthcare professionals. The data demonstrate that weight loss and physical activity can prevent and treat obesity-related coronary heart disease risk factors and should be considered a primary therapy for obese patients with cardiovascular disease.

Eckel RH. · No affiliation provided · Arterioscler Thromb Vasc Biol. · Pubmed #11304458 links to  free full text

This publication has no abstract.

Capell WH, Eckel RH. · No affiliation provided · Curr Diab Rep. · Pubmed #16898578 No free full text.

Abstract: Hypertriglyceridemia is a disorder commonly encountered in clinical practice. Treatment of this condition aims to prevent the major complications of hypertriglyceridemia, which differ depending on whether triglyceride elevations are moderate or severe. This review discusses the pathophysiology and clinical consequences of hypertriglyceridemia and outlines treatment approaches based on the degree of triglyceride elevation. Special consideration is given to clinical trials using medications that primarily target triglycerides.

Matthan NR, Welty FK, Barrett PH, Harausz C, Dolnikowski GG, Parks JS, Eckel RH, Schaefer EJ, Lichtenstein AH. · Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston Mass 02111, USA. · Arterioscler Thromb Vasc Biol. · Pubmed #15087307 links to  free full text

Abstract: OBJECTIVE: To determine mechanisms contributing to decreased high-density lipoprotein cholesterol (HDL-C) and increased low-density lipoprotein cholesterol (LDL-C) concentrations associated with hydrogenated fat intake, kinetic studies of apoA-I, apoB-100, and apoB-48 were conducted using stable isotopes. METHODS AND RESULTS: Eight postmenopausal hypercholesterolemic women were provided in random order with 3 diets for 5-week periods. Two-thirds of the fat was soybean oil (unsaturated fat), stick margarine (hydrogenated fat), or butter (saturated fat). Total and LDL-C levels were highest after the saturated diet (P<0.05; saturated versus unsaturated) whereas HDL-C levels were lowest after the hydrogenated diet (P<0.05; hydrogenated versus saturated). Plasma apoA-I levels and pool size (PS) were lower, whereas apoA-I fractional catabolic rate (FCR) was higher after the hydrogenated relative to the saturated diet (P<0.05). LDL apoB-100 levels and PS were significantly higher, whereas LDL apoB-100 FCR was lower with the saturated and hydrogenated relative to the unsaturated diet. There was no significant difference among diets in apoA-I or B-100 production rates or apoB-48 kinetic parameters. HDL-C concentrations were negatively associated with apoA-I FCR (r=-0.56, P=0.03) and LDL-C concentrations were negatively correlated with LDL apoB-100 FCR (r=-0.48, P=0.05). CONCLUSIONS: The mechanism for the adverse lipoprotein profile observed with hydrogenated fat intake is determined in part by increased apoA-I and decreased LDL apoB-100 catabolism.

Capell WH, DeSouza CA, Poirier P, Bell ML, Stauffer BL, Weil KM, Hernandez TL, Eckel RH. · Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA. · Arterioscler Thromb Vasc Biol. · Pubmed #12588776 links to  free full text

Abstract: OBJECTIVE: The objective of this study was to investigate the effects of lowering plasma triglycerides (TGs) on endothelial function and gain insight into the role played by free fatty acids (FFAs) in hypertriglyceridemia-associated vascular dysfunction. METHODS AND RESULTS: Eleven hypertriglyceridemic subjects without coronary artery disease, diabetes, elevated low-density lipoprotein cholesterol, tobacco use, or hypertension were studied using a randomized, double-blinded, crossover design (fenofibrate and placebo, 14 days). After each regimen, forearm blood flow was assessed by plethysmography in response to arterial acetylcholine, nitroprusside, and verapamil infusion. Hourly plasma TGs, FFA, glucose, and insulin were measured during a 24-hour feeding cycle to characterize the metabolic environment. Changes in plasma FFA after intravenous heparin were used to estimate typical FFA accumulation in the luminal endothelial microenvironment. Fenofibrate lowered plasma TG (P<0.001), total cholesterol (P<0.01), and apolipoprotein B (P<0.01) without altering high-density lipoprotein or low-density lipoprotein cholesterol concentrations. Forearm blood flow in response to acetylcholine (P<0.0001), nitroprusside (P<0.001), and verapamil (P<0.0001) improved after fenofibrate. Fenofibrate lowered 24-hour (P<0.0001) and post-heparin (P<0.001) TG and tended to lower 24-hour (P=0.054) and post-heparin (P=0.028) FFA. CONCLUSIONS: Vascular smooth muscle function significantly improves after lowering plasma TG without changes in confounding lipoproteins or insulin resistance. The data raise additional questions regarding the role of FFA in hypertriglyceridemia-associated vascular dysfunction.

Plenge JK, Hernandez TL, Weil KM, Poirier P, Grunwald GK, Marcovina SM, Eckel RH. · Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Health Sciences Center, Denver, Colo 80262, USA. · Circulation. · Pubmed #12234946 links to  free full text

Abstract: BACKGROUND: The early response of C-reactive protein to initiation of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) is not known. The purpose of this study was to determine the rate at which highly sensitive C-reactive protein (hsCRP) levels change after initiation of simvastatin and whether this occurs independently of the change in LDL cholesterol. METHODS AND RESULTS: The study was a crossover, double-blind design including 40 subjects with elevated LDL cholesterol. Subjects were randomly assigned to 1 of 2 groups: simvastatin 40 mg for 14 days, then placebo for 14 days, or placebo first, then simvastatin. Simvastatin decreased LDL cholesterol by 56+/-4 mg/dL (P<0.0001) at day 7 and by an additional 8+/-3 mg/dL (P=0.02) at day 14. Baseline log(hsCRP) levels were similar in the 2 groups. By day 14, log(hsCRP) was significantly lower in patients on simvastatin when compared with placebo (P=0.011). Although there was no significant difference in fibrinogen levels, simvastatin produced a modest increase in log[lipoprotein(a)] (P=0.03) at days 7 and 14. There were no relationships between the decrease in LDL cholesterol and the decrease in hsCRP. CONCLUSIONS: Simvastatin lowers hsCRP by 14 days, independent of its effect on LDL cholesterol. This rapid impact of a statin on hsCRP has potential implications in the management of acute coronary syndromes.

Maahs DM, Wadwa RP, McFann K, Nadeau K, Williams MR, Eckel RH, Klingensmith GJ. · Barbara Davis Center for Childhood Diabetes and the Department of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado 80045, USA. · J Pediatr. · Pubmed #17236891 No free full text.

Abstract: OBJECTIVE: Because cardiovascular disease (CVD) is the leading cause of death in patients with type 1 diabetes (T1D) and dyslipidemia is an important CVD risk factor, we investigated dyslipidemia and its treatment in children with T1D. STUDY DESIGN: Subjects had T1D (n = 360), repeated lipid measurements (n = 1095; mean, 3.04 +/- 0.94; range, 2 to 11), and were seen between 1994 and 2004. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL), and non-HDL cholesterol (non-HDL) were categorized on the basis of published guidelines. Age, diabetes duration, sex, body mass index, HbA1c, and lipid-lowering medication use were recorded. Predictors of TC, HDL, and non-HDL were determined. RESULTS: Sustained abnormalities existed for TC > or = 200 mg/dL (16.9%); HDL < 35 mg/dL (3.3%); and non-HDL > or = 130 mg/dL (27.8%), > or = 160 mg/dL (10.6%), and > or = 190 mg/dL (3.3%). Lipid-lowering medications were started on 23 patients. In mixed model longitudinal data analyses, HbA1c was significantly related to TC and non-HDL. Body mass index z-score was inversely related to HDL. CONCLUSIONS: In this retrospective, longitudinal study of pediatric patients with T1D with repeated lipid measurements, sustained abnormal levels for TC, HDL, and non-HDL were present. Prospective longitudinal data for dyslipidemia in youth with T1D are needed.

Pulawa LK, Jensen DR, Coates A, Eckel RH. · Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA. · J Lipid Res. · Pubmed #17018885 links to  free full text

Abstract: LPL and its specific physiological activator, apolipoprotein C-II (apoC-II), regulate the hydrolysis of triglycerides (TGs) from circulating TG-rich lipoproteins. Previously, we developed a skeletal muscle-specific LPL transgenic mouse that had lower plasma TG levels. ApoC-II transgenic mice develop hypertriglyceridemia attributed to delayed clearance. To investigate whether overexpression of LPL could correct this apoC-II-induced hypertriglyceridemia, mice with overexpression of human apoC-II (CII) were cross-bred with mice with two levels of muscle-specific human LPL overexpression (LPL-L or LPL-H). Plasma TG levels were 319 +/- 39 mg/dl in CII mice and 39 +/- 5 mg/dl in wild-type mice. Compared with CII mice, apoC-II transgenic mice with the higher level of LPL overexpression (CIILPL-H) had a 50% reduction in plasma TG levels (P = 0.013). Heart LPL activity was reduced by approximately 30% in mice with the human apoC-II transgene, which accompanied a more modest 10% decrease in total LPL protein. Overexpression of human LPL in skeletal muscle resulted in dose-dependent reduction of plasma TGs in apoC-II transgenic mice. Along with plasma apoC-II concentrations, heart and skeletal muscle LPL activities were predictors of plasma TGs. These data suggest that mice with the human apoC-II transgene may have alterations in the expression/activity of endogenous LPL in the heart. Furthermore, the decrease of LPL activity in the heart, along with the inhibitory effects of excess apoC-II, may contribute to the hypertriglyceridemia observed in apoC-II transgenic mice.

Capell WH, Eckel RH. · Division of Endocrinology, Metabolism, and Diabetes at the University of Colorado at Denver and Health Sciences Center, CO, USA. · Nat Clin Pract Endocrinol Metab. · Pubmed #16929366 No free full text.

Abstract: Background A 53-year-old man with a history of hypertension and gout was referred to our clinic for severe hypertriglyceridemia, diagnosed 3 years previously. He was asymptomatic and had no history of abdominal pain, pancreatitis or diabetes, but consumed six cans of beer per night. Over the previous 2 years, he had been treated unsuccessfully with multiple medications; during this period his fasting triglycerides ranged from 5.41 mM to 55.04 mM (479 to 4,871 mg/dl).Investigations Physical examination including fundoscopy, medication review, and laboratory tests.Diagnosis Severe hypertriglyceridemia due to a genetic combined hyperlipidemia, exacerbated by persistent excessive alcohol intake and metabolic syndrome.Management Cessation of alcohol intake, initiation of a fat-restricted diet, and fibrate therapy, with close follow-up. Once serum triglycerides were controlled, attention was turned to lowering LDL-cholesterol concentration according to The National Cholesterol Education Program, Adult Treatment Panel III guidelines.

Wadwa RP, Kinney GL, Maahs DM, Snell-Bergeon J, Hokanson JE, Garg SK, Eckel RH, Rewers M. · Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East 9th Ave., Box B140, Denver, CO 80262, USA. · Diabetes Care. · Pubmed #15855566 links to  free full text

Abstract: OBJECTIVE: Dyslipidemia is a preventable major risk factor for coronary heart disease (CHD). Despite an increased risk of CHD in type 1 diabetes, little is known concerning awareness and adequacy of dyslipidemia treatment in this population. In this report, we describe the prevalence of dyslipidemia and adequacy of pharmacological treatment in patients with type 1 diabetes and comparable nondiabetic subjects. RESEARCH DESIGN AND METHODS: From 2000 to 2002, the Coronary Artery Calcification in Type 1 Diabetes study obtained fasting lipid profiles in 1,416 individuals aged 19-56 years with no history of CHD: 652 type 1 diabetic patients (46% men, mean age 37 +/- 9 years) and 764 nondiabetic control subjects (50% men, mean age 39 +/- 9 years). These data combined with patient questionnaire results were used to determine prevalence of dyslipidemia and adequacy of pharmacological treatment. For all subjects, dyslipidemia was defined using National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: Type 1 diabetic subjects had significantly less dyslipidemia than nondiabetic control subjects (47 vs. 58%, P < 0.001), and a higher percentage of those with abnormal lipids were aware of (52 vs. 34%, P < 0.0001), on medication for (36 vs. 9%, P < 0.0001), and in control of their lipid levels (15 vs. 1.4%, P < 0.001). Of those on treatment, control was achieved in 41% of type 1 diabetic subjects and 15% of nondiabetic participants (P < 0.01). CONCLUSIONS: Dyslipidemia, a major risk factor for CHD, remains largely undiagnosed and undertreated in high-risk populations, such as patients with type 1 diabetes.

Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J. · Department of Neurology, Northwestern University, Evanston, IL 60208, USA. · Science. · Pubmed #15845877 links to  free full text

Abstract: The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.

Davies PJ, Berry SA, Shipley GL, Eckel RH, Hennuyer N, Crombie DL, Ogilvie KM, Peinado-Onsurbe J, Fievet C, Leibowitz MD, Heyman RA, Auwerx J. · Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, Texas 77225, USA. · Mol Pharmacol. · Pubmed #11160850 links to  free full text

Abstract: Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both normal and diabetic rodents. Administration of a rexinoid such as LG100268 (LG268) to normal or diabetic rats results in a rapid increase in serum triglyceride levels. LG268 has no effect on hepatic triglyceride production but suppresses post-heparin plasma lipoprotein lipase (LPL) activity suggesting that the hypertriglyceridemia results from diminished peripheral processing of plasma very low density lipoproteins particles. Treatment of diabetic rats with rexinoids suppresses skeletal and cardiac muscle but not adipose tissue LPL activity. This effect is independent of changes in LPL mRNA. In C2C12 myocytes, LG268 suppresses the level of cell surface (i.e., heparin-releasable) LPL activity without altering LPL mRNA. This effect is very rapid (t(1/2) = 2 h) and is blocked by the transcriptional inhibitor actinomycin D. These studies demonstrate that RXR ligands can have dramatic effects on the post-translational processing of LPL and suggest that skeletal muscle may be an important target of rexinoid action. In addition, these data underscore that the metabolic consequences of RXR activation are distinct from either retinoic acid receptor or peroxisome proliferator-activated receptor activation.

Eckel RH. · Division of Endocrinology, Metabolism and Diabetes, University of Colorado at Denver & Health Sciences Center, PO Box 6511, MS8106, Aurora, Colorado 80045, USA. · Proc Nutr Soc. · Pubmed #17343775 No free full text.

Abstract: The metabolic syndrome represents a summation of obesity-driven risk factors for atherosclerotic CVD and type 2 diabetes. Definitions of the syndrome vary but in general agree closely in identifying subjects. The relationships between the metabolic syndrome and atherosclerotic CVD and diabetes also vary, with relative risks of approximately 1.5-3.0 and approximately 3.0-5.0 respectively. Insulin resistance appears to explain much of the pathophysiology of the syndrome. Both increased fatty acid flux and an excess of circulating pro-inflammatory cytokines are likely mediators. With increased waist circumference, increases in fatty acid delivery to the liver result in higher rates of hepatic glucose production and increases in the secretion of apoB-containing lipoproteins. Concomitant changes in HDL ensue, including a replacement of the cholesterol content with TAG, an accelerated clearance from the plasma and thus a reduced number of HDL particles. Typically also present are increases in small dense LDL. Hypertension in part relates to the insulin resistance, but may involve other mechanisms. Impaired fasting glucose often relates to defects in insulin secretion in addition to insulin resistance, and probably more than any other component of the syndrome predicts the increased incidence of type 2 diabetes. Although not included in the diagnostic criteria, increases in pro-inflammatory cytokines and pro-thrombotic factors, in addition to decreases in plasma adiponectin, may also contribute to the increased incidence of atherosclerotic CVD and diabetes. In general, the greater the number of metabolic syndrome components, the greater the risk for these outcomes. The cytokines and pro-thrombotic factors also appear to contribute.