Big Fish or No Fish; Eicosapentaenoic Acid and Cardiovascular Disease.

Benefits of omega 3 fatty acids for cardiovascular and other diseases have been touted for more than 50 years. The one clear clinical benefit of these lipids is the reduction of circulating levels of triglycerides, making them a useful approach for the prevention of pancreatitis in severely hypertriglyceridemic patients. After a series of spectacularly failed clinical trials that were criticized for the choice of subjects and doses of omega 3 fatty acids used, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) using a high dose of icosapent ethyl (IPE) reported a reduction in cardiovascular disease (CVD) events. However, this trial has generated controversy due to the use of mineral oil in the control group and the associated side effects of the IPA. This review will focus on the following topics: What are the epidemiologic data suggesting a benefit of omega 3 fatty acids? What might be the mechanisms for these benefits? Why have the clinical trials failed to resolve whether these fatty acids provide benefit? What choices should a clinician consider?

Short-Term Acyl-CoA:Cholesterol Acyltransferase Inhibition, Combined with Apoprotein A1 Overexpression, Promotes Atherosclerosis Inflammation Resolution in Mice.

Acyl-CoA:cholesterol acyltransferase (ACAT) mediates cellular cholesterol esterification. In atherosclerotic plaque macrophages, ACAT promotes cholesteryl ester accumulation, resulting in foam cell formation and atherosclerosis progression. Its complete inactivation in mice, however, showed toxic effects because of an excess of free cholesterol (FC) in macrophages, which can cause endoplasmic reticulum stress, cholesterol crystal formation, and inflammasome activation. Our previous studies showed that long-term partial ACAT inhibition, achieved by dietary supplementation with Fujirebio F1394, delays atherosclerosis progression in apoprotein E-deficient (Apoe -/-) mice by reducing plaque foam cell formation without inflammatory or toxic effects. Here, we determined whether short-term partial inhibition of ACAT, in combination with an enhanced systemic FC acceptor capacity, has synergistic benefits. Thus, we crossbred Apoe -/- with human apoprotein A1-transgenic (APOA1 tg/tg) mice, which have elevated cholesterol-effluxing high-density lipoprotein particles, and subjected Apoe -/- and APOA1 tg/tg/Apoe -/- mice to an atherogenic diet to develop advanced plaques. Then mice were either euthanized (baseline) or fed purified standard diet with or without F1394 for 4 more weeks. Plaques of APOA1 tg/tg/Apoe -/- mice fed F1394 showed a 60% reduction of macrophages accompanied by multiple other benefits, such as reduced inflammation and favorable changes in extracellular composition, in comparison with Apoe -/- baseline mice. In addition, there was no accumulation of cholesterol crystals or signs of toxicity. Overall, these results show that short-term partial ACAT inhibition, coupled to increased cholesterol efflux capacity, favorably remodels atherosclerosis lesions, supporting the potential of these combined therapies in the treatment of advanced atherosclerosis. SIGNIFICANCE STATEMENT: Short-term pharmacological inhibition of acyl-CoA:cholesterol acyltransferase-mediated cholesterol esterification, in combination with increased free cholesterol efflux acceptors, has positive effects in mice by 1) reducing the inflammatory state of the plaque macrophages and 2) favoring compositional changes associated with plaque stabilization. These effects occur without toxicity, showing the potential of these combined therapies in the treatment of advanced atherosclerosis.

ß-Carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice.

Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of CVDs, and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma ß-carotene with atherosclerosis, and we recently showed that ß-carotene oxygenase 1 (BCO1) activity, responsible for ß-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact ß-carotene or vitamin A affects atherosclerosis progression in the atheroprone LDLR-deficient mice. Compared with control-fed Ldlr-/- mice, ß-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and reduced plasma cholesterol levels. These changes were absent in Ldlr-/- /Bco1-/- mice despite accumulating ß-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism.

Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine

OBJECTIVE: Statin intolerance, whether real or perceived, is a growing issue in clinical practice. Our aim was to evaluate the effects of reduced-dose statin therapy complemented with nutraceuticals. METHODS: First phase: Initially, 53 type 2 diabetic statin-treated patients received a supplementation with fish oil (1.7 g EPA + DHA/day), chocolate containing plant sterols (2.2 g/day), and green tea (two sachets/day) for 6 weeks. Second phase: "Good responders" to supple-mentation were identified after multivariate analysis (n»10), and recruited for a pilot protocol of statin dose reduction. "Good responders" were then provided with supplementation for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6e12.RESULTS: First phase: After 6 weeks of supplementation, plasma LDL-C (-13.7% 3.7,P».002) and C-reactive protein ( 35.5% 5.9,P».03) were reduced. Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced bycholesterol absorption rate rather than its synthesis. Second phase: no difference was observed for plasma lipids, inflammation, cholesterol effluxcapacity, or HDL particles after statin dose reduction when compared to standard therapy. CONCLUSIONS: Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. Further studies should elucidate "good responders" profile as a tool for personalized medicine. This may be particularly helpful in the many patients with or at risk for CVD who cannot tolerate high dose statin therapy. Trial registration: ClinicalTrials.gov, NCT02732223.

Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine.

OBJECTIVE: Statin intolerance, whether real or perceived, is a growing issue in clinical practice. Our aim was to evaluate the effects of reduced-dose statin therapy complemented with nutraceuticals. METHODS: First phase: Initially, 53 type 2 diabetic statin-treated patients received a supplementation with fish oil (1.7 g EPA + DHA/day), chocolate containing plant sterols (2.2 g/day), and green tea (two sachets/day) for 6 weeks. Second phase: "Good responders" to supplementation were identified after multivariate analysis (n = 10), and recruited for a pilot protocol of statin dose reduction. "Good responders" were then provided with supplementation for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6-12. RESULTS: First phase: After 6 weeks of supplementation, plasma LDL-C (-13.7% ± 3.7, P = .002) and C-reactive protein (-35.5% ± 5.9, P = .03) were reduced. Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced by cholesterol absorption rate rather than its synthesis. Second phase: no difference was observed for plasma lipids, inflammation, cholesterol efflux capacity, or HDL particles after statin dose reduction when compared to standard therapy. CONCLUSIONS: Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. Further studies should elucidate "good responders" profile as a tool for personalized medicine. This may be particularly helpful in the many patients with or at risk for CVD who cannot tolerate high dose statin therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02732223.

Preclinical mouse models and methods for the discovery of the causes and treatments of atherosclerosis.

INTRODUCTION: Atherosclerosis is the leading cause of death in the Western world. Despite huge advances in understanding its pathophysiological mechanisms, current treatment is mostly based on 'traditional' risk factors. The introduction of statins more than 20 years ago reduced morbidity and mortality of atherosclerosis by 30%, leaving a residual cardiovascular risk. Therefore, efforts continue toward the development of novel therapies that can be added to established treatments. Besides targeting dyslipidemia, recent focus has been put on preventing or resolving inflammatory processes involved in atherosclerosis. AREAS COVERED: The article discusses therapeutic and diagnostic targets in atherosclerosis and how they can be discovered and studied in preclinical animal models. The roles of immune cells, specifically macrophages and monocytes, in plaque inflammation are discussed. The article also describes current preclinical models of atherosclerosis, specifically the mouse, study designs (for progression and regression studies), basic and advanced methods of analysis of atherosclerotic lesions, and discusses the challenges of translating the findings to humans. EXPERT OPINION: Advances in genomics, proteomics, lipidomics and the development of high-throughput screening techniques help to improve our understanding of atherosclerosis disease mechanisms immensely and facilitate the discovery of new diagnostic and therapeutic targets. Preclinical studies in animals are still indispensable to uncover pathways involved in atherosclerotic disease and to evaluate novel drug targets. The translation of these targets, however, from animal studies to humans remains challenging. There is a strong need for novel biomarkers that can be used to prove the concept of a new target in humans.

Oxidation, lipoproteins, and atherosclerosis: which is wrong, the antioxidants or the theory?

PURPOSE OF REVIEW: Paradoxically, many well-established components of the heart-healthy lifestyle are pro-oxidant, including polyunsaturated fat and moderate alcohol consumption. Moreover, antioxidant supplements have failed to decrease cardiovascular risk in extensive human clinical trials to date. Recent progress in understanding the roles of oxidants in regulating VLDL secretion and as essential signaling molecules supports the concept that oxidation may be beneficial in certain circumstances but damaging in others. We summarize recent data on the roles played by oxidative metabolism in different tissues and pathways, and address whether it is currently advisable to use antioxidant supplements to reduce cardiovascular risk. RECENT FINDINGS: Our recent study reported that in liver cells, polyunsaturated fatty acids increased reactive oxygen species, which in turn lowered the secretion of the atherogenic lipoprotein, VLDL, in vitro and in vivo. Antioxidant treatments prevented VLDL-lowering effects of polyunsaturated fatty acids in vitro, suggesting that supplemental antioxidants could either raise apolipoprotein-B-lipoprotein plasma levels in vivo, or impair the response to lipid-lowering therapies. The failure of antioxidants to decrease cardiovascular disease risk in many trials is also discussed in the context of current models for atherosclerosis progression and regression. SUMMARY: Oxidation includes distinct biochemical reactions, and it is overly simplistic to lump them into a unitary process that affects all cell types and metabolic pathways adversely. Guidelines for diet should adhere closely to what has been clinically proved, and by this standard there is no basis to recommend antioxidant use, beyond what is inherent to the 'heart healthy' diet in order to benefit cardiovascular health.