Warren H. Capell

Short-Term Triglyceride Lowering With Fenofibrate Improves Vasodilator Function in Subjects With Hypertriglyceridemia

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.

Lack of suppression of circulating free fatty acids and hypercholesterolemia during weight loss on a high-fat, low-carbohydrate diet

BACKGROUND Little is known about the comparative effect of weight-loss diets on metabolic profiles during dieting. OBJECTIVE The purpose of this study was to compare the effect of a low-carbohydrate diet (< or =20 g/d) with a high-carbohydrate diet (55% of total energy intake) on fasting and hourly metabolic variables during active weight loss. DESIGN Healthy, obese adults (n = 32; 22 women, 10 men) were randomly assigned to receive either a carbohydrate-restricted diet [High Fat; mean +/- SD body mass index (BMI; in kg/m(2)): 35.8 +/- 2.9] or a calorie-restricted, low-fat diet (High Carb; BMI: 36.7 +/- 4.6) for 6 wk. A 24-h in-patient feeding study was performed at baseline and after 6 wk. Glucose, insulin, free fatty acids (FFAs), and triglycerides were measured hourly during meals, at regimented times. Remnant lipoprotein cholesterol was measured every 4 h. RESULTS Patients lost a similar amount of weight in both groups (P = 0.57). There was an absence of any diet treatment effect between groups on fasting triglycerides or on remnant lipoprotein cholesterol, which was the main outcome. Fasting insulin decreased (P = 0.03), and both fasting (P = 0.040) and 24-h FFAs (P < 0.0001) increased within the High Fat group. Twenty-four-hour insulin decreased (P < 0.05 for both groups). Fasting LDL cholesterol decreased in the High Carb group only (P = 0.003). In both groups, the differences in fasting and 24-h FFAs at 6 wk were significantly correlated with the change in LDL cholesterol (fasting FFA: r = 0.41, P = 0.02; 24-h FFA: r = 0.52, P = 0.002). CONCLUSIONS Weight loss was similar between diets, but only the high-fat diet increased LDL-cholesterol concentrations. This effect was related to the lack of suppression of both fasting and 24-h FFAs.

A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative

Peripheral artery disease affects >200 million people worldwide and is associated with significant limb and cardiovascular morbidity and mortality. Limb revascularization is recommended to improve function and quality of life for symptomatic patients with peripheral artery disease with intermittent claudication who have not responded to medical treatment. For patients with critical limb ischemia, the goals of revascularization are to relieve pain, help wound healing, and prevent limb loss. The baseline risk of cardiovascular and limb-related events demonstrated among patients with stable peripheral artery disease is elevated after revascularization and related to atherothrombosis and restenosis. Both of these processes involve platelet activation and the coagulation cascade, forming the basis for the use of antiplatelet and anticoagulant therapies to optimize procedural success and reduce postprocedural cardiovascular risk. Unfortunately, few high-quality, randomized data to support use of these therapies after peripheral artery disease revascularization exist, and much of the rationale for the use of antiplatelet agents after endovascular peripheral revascularization is extrapolated from percutaneous coronary intervention literature. Consequently, guideline recommendations for antithrombotic therapy after lower limb revascularization are inconsistent and not always evidence-based. In this context, the purpose of this structured review is to assess the available randomized data for antithrombotic therapy after peripheral arterial revascularization, with a focus on clinical trial design issues that may affect interpretation of study results, and highlight areas that require further investigation.

Severe hypertriglyceridemia with a history of treatment failure

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.

Ethical conduct of palliative care research: Enhancing communication between investigators and institutional review boards

Palliative care has faced moral and ethical challenges when conducting research involving human subjects. There are currently no resources to guide institutional review boards (IRBs) in applying standard ethical principles and terms-in a specific way-to palliative care research. Using as a case study a recently completed multisite palliative care clinical trial, this article provides guidance and recommendations for both IRBs and palliative care investigators to facilitate communication and attain the goal of conducting ethical palliative care research and protecting study participants while advancing the science. Beyond identifying current challenges faced by palliative care researchers and IRBs reviewing palliative care research, this article suggests steps that the palliative care research community can take to establish a scientifically sound, stable, productive, and well-functioning relationship between palliative care investigators and the ethical bodies that oversee their work.

Rationale and design for the Vascular Outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD)

Background: Patients with peripheral artery disease (PAD) undergoing a lower‐extremity revascularization are at heightened risk for ischemic cardiac and limb events. Although intensification of antithrombotic therapy after revascularization has demonstrated benefit in coronary disease populations, this approach has not been well studied or shown consistent benefit in PAD. Recent trial evidence demonstrated that a treatment strategy of rivaroxaban added to background antiplatelet therapy reduced ischemic risk in patients following recent acute coronary syndromes, as well as in patients with stable atherosclerotic vascular disease. Whether these benefits extend to the population of patients with symptomatic lower‐extremity PAD undergoing revascularization is the objective of the VOYAGER PAD trial. Study design: VOYAGER PAD is an international randomized, double‐blind, placebo‐controlled trial to evaluate the efficacy and safety of rivaroxaban in symptomatic PAD patients undergoing a peripheral surgical and/or endovascular revascularization. Patients are randomized in a 1:1 ratio to either rivaroxaban 2.5 mg twice daily or placebo, on a background of low‐dose aspirin (100 mg daily). In addition, the use of a limited course of P2Y12 inhibition is allowed at the discretion of the site investigator. The primary efficacy end point is a novel composite of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia, and major amputation of vascular etiology. The primary safety end point is major bleeding according to the Thrombolysis in Myocardial Infarction definition. Enrolment began in August 2015 and will complete randomization of at least 6,500 patients by January 2018. This event‐driven trial is expected to observe outcomes over a mean patient follow‐up of 30 months. Conclusions: VOYAGER PAD is evaluating the efficacy of rivaroxaban added to background antiplatelet therapy to reduce major cardiovascular and limb ischemic vascular outcomes in the high‐risk population of PAD patients undergoing peripheral revascularization.

Plant sterols added to combination statin and colesevelam hydrochloride therapy failed to lower low-density lipoprotein cholesterol concentrations

BACKGROUND The purpose of this study was to evaluate the effects on LDL-cholesterol (LDL-C) from addition of plant sterol treatment to patients with dyslipidemia already taking a statin and colesevelam hydrochloride (HCl). Current cholesterol treatment guidelines recommend use of plant stanols/sterols to help reach LDL-C goals in patients taking other lipid-lowering therapies. Previous data demonstrate LDL-C lowering by adding stanols/sterols to statins. However, data are conflicting regarding the benefit from combination stanols/sterols with bile acid sequestrants. METHODS Fifty-five subjects on a stable dose of statin completed a 10-week, double-blind, randomized study of colesevelam HCl 3.75 g/day alone for 4 weeks, then 6 weeks of additional 2 g/day plant sterol-fortified orange juice (S-OJ) or placebo orange juice (P-OJ). Serum total cholesterol (TC), LDL-C, HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline, 4 weeks, and 10 weeks. RESULTS Baseline LDL-C measurements (mean ± SD) were similar between S-OJ and P-OJ groups (122 ± 20 vs 126 ± 24 mg/dL, respectively). Four weeks of colesevelam HCl in combination with a statin significantly reduced TC, LDL-C, and ApoB (9.6%, P < 0.001; 21.9%, P < 0.001; and 8.5%, P = 0.001, respectively), and significantly increased HDL-C (6.2%, P = 0.002) and TG (18.8%, P = 0.002). However, compared to P-OJ, 10 weeks of S-OJ produced no effect on any outcome parameter beyond that of colesevelam HCl. CONCLUSION Plant S-OJ appears to be ineffective at further reducing LDL-C when added to statin and colesevelam HCl combination therapy in patients with dyslipidemia.

Fatty acids increase glucose uptake and metabolism in C2C12 myoblasts stably transfected with human lipoprotein lipase

Cellular effects of FFA might differ from those of lipoprotein triglyceride (TG)-derived fatty acids (TGFA). The aim of the current study was to examine the relationship between lipoprotein lipase (LPL) expression, TGFA, or FFA availability and glucose metabolism in the absence of insulin in C2C12 myoblasts. Control myoblasts or myoblasts stably transfected with human lipoprotein lipase (C2/LPL; 15-fold greater LPL activity) were incubated for 12 h in fetal bovine serum-free medium in the absence or presence of Intralipid-20. Intracellular retention of labeled medium glucose was assessed in a subset of experiments. In the presence of Intralipid, medium glucose disappearance was increased in C2/LPL cells but not in control cells. In both cell types, glucose label retention in cellular TG was increased in the presence of Intralipid; incubation with albumin-bound oleate produced similar results. In the presence of Intralipid, the LPL hydrolytic inhibitor tetrahydrolipstatin blocked excess glucose retention in cellular TG but did not significantly decrease glucose disappearance in C2/LPL cells. Changes in glucose transport or hexokinase II did not explain the altered glucose disappearance in C2/LPL cells. Our results suggest that LPL overexpression in these cells leads to chronic metabolic adaptations that alter glucose uptake and retention.