Intestinal lymphatic vessels and their role in chylomicron absorption and lipid homeostasis Purpose of review In this review, we describe novel findings related to intestinal lipid transport in lymphatic vessels. Recent findings Studies have shown that chylomicron entry to lacteals and lymph movement in intestinal lymphatic capillaries is an active process. Regulators of this intestinal chylomicron transport include among others the autonomous nervous system, transcription factors like PLAGL2, and molecular regulators, such as VEGF-A/Nrp1/VEGFR1, VEGF-C/VEGFR3, DLL4, CALCRL and GLP-2. Chylomicron transport in intestinal lymphatics is now emerging not only as an option for drug delivery but also as a new candidate for drug targeting in lipid-related disorders. Summary Dysfunctions of lymphatic lipid transport can result in conditions such as dyslipidaemia. Intestinal lymphatics also provide several potential therapeutic possibilities: molecular regulation of lacteal cell-to-cell junctioning and lymph flow could provide new ways of treating conditions like hyperlipidaemia and associated diseases, such as atherosclerosis and other cardiovascular diseases, obesity, diabetes and fatty-liver disease. The intestinal lymphatic system can also be employed to deliver lipid nanoparticles as drug carriers to the venous circulation for improved treatment outcome. These findings highlight the importance and need for research on the different players of intestinal lymphatics in dietary lipid handling and therapeutic applications. Correspondence to Seppo Ylä-Herttuala, MD, PhD, FESC, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: seppo.ylaherttuala@uef.fi Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Monocytes and macrophages in atherogenesis Purpose of review Monocytes and macrophages are key players in the pathogenesis of atherosclerosis and dictate atherogenesis growth and stability. The heterogeneous nature of myeloid cells concerning their metabolic and phenotypic function is increasingly appreciated. This review summarizes the recent monocyte and macrophage literature and highlights how differing subsets contribute to atherogenesis. Recent findings Monocytes are short-lived cells generated in the bone marrow and released to circulation where they can produce inflammatory cytokines and, importantly, differentiate into long-lived macrophages. In the context of cardiovascular disease, a myriad of subtypes, exist with each differentially contributing to plaque development. Herein we describe recent novel characterizations of monocyte and macrophage subtypes and summarize the recent literature on mediators of myelopoiesis. Summary An increased understanding of monocyte and macrophage phenotype and their molecular regulators is likely to translate to the development of new therapeutic targets to either stem the growth of existing plaques or promote plaque stabilization. Correspondence to Tessa J. Barrett, New York University School of Medicine, 435 East 30th St, Science Building, 7K, New York, NY 10016, USA. E-mail: tessa.barrett@nyulangone.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The role of the small intestine in modulating metabolism and inflammation in atherosclerosis and cancer Purpose of review To discuss recent findings on the importance of the small intestine in modulating metabolism and inflammation in atherosclerosis and cancer. Recent findings Integrin β7+ natural gut intraepithelial T cells modulated metabolism and accelerated atherosclerosis in mice. Reducing the generation of lysophospholipids in the small intestine mimicked bariatric surgery and improved diabetes. Enterocyte-specific knockdown of stearoyl-CoA desaturase-1 significantly improved dyslipidemia in LDL receptor null (Ldlr−/−) mice fed a Western diet. Adding a concentrate of tomatoes transgenic for the apolipoprotein A-I mimetic peptide 6F to the chow of wild-type mice altered lipid metabolism in the small intestine, preserved Notch signaling and reduced tumor burden in mouse models. The phospholipid-remodeling enzyme Lpcat3 regulated intestinal stem cells and progenitor cells by stimulating cholesterol biosynthesis; increasing cholesterol in the diet or through genetic manipulation promoted tumorigenesis in Apcmin+ mice. Summary The small intestine is important for regulating metabolism and inflammation in animal models of both atherosclerosis and cancer. Correspondence to Alan M. Fogelman, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, Box 951736, Los Angeles, CA 90095-1736, USA. Tel: +1 310 825 6058; fax: +1 310 206 3489; e-mail: afogelman@mednet.ucla.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Triglycerides and endothelial function: molecular biology to clinical perspective Purpose of review Recently, a high level of triglycerides has attracted much attention as an important residual risk factor of cardiovascular events. We will review and show the mechanisms underlying the association of endothelial dysfunction with hypertriglyceridemia and present clinical evidence for a relationship between endothelial function and triglycerides. Recent findings Clinical studies have shown that hypertriglyceridemia is associated with endothelial dysfunction. It is likely that hypertriglyceridemia impairs endothelial function through direct and indirect mechanisms. Therefore, hypertriglyceridemia is recognized as a therapeutic target in the treatment of endothelial dysfunction. Although experimental and clinical studies have shown that fibrates and omega-3 fatty acids not only decrease triglycerides but also improve endothelial function, the effects of these therapies on cardiovascular events are controversial. Summary Accumulating evidence suggests that hypertriglyceridemia is an independent risk factor for endothelial dysfunction. Triglycerides should be considered more seriously as a future target to reduce cardiovascular events. Results of ongoing studies may show the benefit of lowering triglycerides and provide new standards of care for patients with hypertriglyceridemia possibly through improvement in endothelial function. Correspondence to Yukihito Higashi, MD, PhD, FAHA, Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Tel: +81 82 257 5831; fax: +81 82 257 5831; e-mail: yhigashi@hiroshima-u.ac.jp Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Neointimal hyperplasia: are fatty acid transport proteins a new therapeutic target? Purpose of review High-fat diets contribute to hyperlipidemia and dysregulated metabolism underlying insulin resistant states and cardiovascular diseases. Neointimal hyperplasia is a significant resulting morbidity. Increased fatty acid (FA) levels lead to dysfunctional endothelium, defined as activated, proinflammatory and prothrombotic. The purpose of this review is to assess the recent literature on the emerging concept that uptake of FA into many tissues is regulated at the endothelial level, and this in turn contributes to endothelial dysfunction, an initiating factor in insulin resistant states, atherosclerosis and neointimal hyperplasia. Recent findings Studies support the role of endothelial FA uptake proteins as an additional level of regulation in tissue FA uptake. These proteins include CD36, FA transport proteins, FA-binding proteins and caveolin-1. In many cases, inappropriate expression of these proteins can result in a change in FA and glucose uptake, storage and utilization. Accumulation of plasma FA is one mechanism by which alterations in expression of FA uptake proteins can lead to endothelial dysfunction; changes in tissue substrate metabolism leading to inflammation are also implicated. Summary Identification of the critical players and regulators can lead to therapeutic targeting to reduce endothelial dysfunction and sequela such as insulin resistance and neointimal hyperplasia. Correspondence to Maria Febbraio, Department of Dentistry, Faculty of Medicine & Dentistry, University of Alberta, 7020M Katz Group Centre for Pharmacy & Health Research, 11361 87th Avenue, Edmonton, AB, Canada T6G 2E1. Tel: +1 780 492 3066; e-mail: febbraio@ualberta.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Maximizing the benefits of cholesterol-lowering drugs Purpose of review Drugs to lower LDL-C levels are very widely used. In this brief review, I will use selected recent studies to delineate several important principles that provide a rationale for how to maximize the benefits of using LDL-C lowering drugs to reduce cardiovascular disease. The focus will be on using statins, ezetimibe, and PCSK9 monoclonal antibodies as recent studies have predominantly utilized these agents. Recent findings The key principles to consider when using LDL-C-lowering drugs to reduce cardiovascular disease are: the lower the LDL-C the better; the sooner and the longer one lowers LDL-C the better; the higher the risk of cardiovascular disease the greater the absolute benefit; the higher the baseline LDL-C the greater the absolute benefit; and compared with the benefits of cholesterol-lowering drugs on reducing cardiovascular disease the risk of side effects is very modest. Summary Understanding and employing these key concepts in caring for patients will allow one to use cholesterol-lowering drugs wisely to maximize the reduction of cardiovascular events. Correspondence to Kenneth R. Feingold, MD, Department of Medicine, University of California, San Francisco, CA 94121, USA. Tel: +1 415 302 8463; e-mail: kenneth.feingold@ucsf.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Trained immunity and atherosclerotic cardiovascular disease Purpose of review The two major challenges in cardiovascular medicine are to refine risk prediction and to improve pharmacological prevention and treatment. The concept of innate immune memory, which is called trained immunity, has the potential to improve clinical practice in these regards. Recent findings Monocytes and macrophages have the capability to develop a long-term proinflammatory and proatherogenic phenotype after brief exposure to inflammatory stimuli, such as oxidized low-density lipoprotein particles. This innate immune memory develops because of rewiring of intracellular metabolic pathways and epigenetic reprogramming of histone modifications. The persistence of circulating hyperresponsive monocytes in vivo is explained by the fact that training occurs in myeloid progenitor cells in the bone marrow. Several recent studies reported the presence of monocytes with a trained immune phenotype in patients with established atherosclerosis, and in patients with an increased risk for atherosclerosis because of dyslipoproteinemia. Summary In monocytes and their bone marrow progenitors, metabolic and epigenetic reprogramming can induce trained immunity, which might contribute to the persistent nonresolving inflammation that characterizes atherosclerosis. These pathways offer exciting novel drug targets to improve the prevention and treatment of cardiovascular disease. Correspondence to Niels P. Riksen, Professor of Vascular Medicine, Department of Internal Medicine, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Tel: +31 24 3618819; fax: +31 24 3616519; e-mail: niels.riksen@radboudumc.nl Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.