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.