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Novel Insights From Human Studies on the Role of High-Density Lipoprotein in Mortality and Noncardiovascular Disease.
Madsen, CM, Varbo, A, Nordestgaard, BG
Arteriosclerosis, thrombosis, and vascular biology. 2021;(1):128-140
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Abstract
The vast majority of research about HDL (high-density lipoprotein) has for decades revolved around the possible role of HDL in atherosclerosis and its therapeutic potential within cardiovascular disease prevention; however, failures with therapies aimed at increasing HDL cholesterol has left questions as to what the role and function of HDL in human health and disease is. Recent observational studies have further shown that extreme high HDL cholesterol is associated with high mortality leading to speculations that HDL could in some instances be harmful. In addition, evidence from observational, and to a lesser extent genetic studies has emerged indicating that HDL might be associated with the development of other major noncardiovascular diseases, such as infectious disease, autoimmune disease, cancer, type 2 diabetes, kidney disease, and lung disease. In this review, we discuss (1) the association between extreme high HDL cholesterol and mortality and (2) the emerging human evidence linking HDL to several major diseases outside the realm of cardiovascular disease.
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High Density Lipoprotein Cholesterol Efflux Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological Aspects and Pharmacological Perspectives.
Adorni, MP, Ronda, N, Bernini, F, Zimetti, F
Cells. 2021;(3)
Abstract
Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of HDL to promote cell cholesterol efflux from cells, has emerged as a better predictor of cardiovascular (CV) risk compared to merely plasma HDL-cholesterol (HDL-C) levels. HDL CEC is impaired in many genetic and pathological conditions associated to high CV risk such as dyslipidemia, chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders, etc. The present review describes the current knowledge on HDL CEC modifications in these conditions, focusing on the most recent human studies and on genetic and pathophysiologic aspects. In addition, the most relevant strategies possibly modulating HDL CEC, including lifestyle modifications, as well as nutraceutical and pharmacological interventions, will be discussed. The objective of this review is to help understanding whether, from the current evidence, HDL CEC may be considered as a valid biomarker of CV risk and a potential pharmacological target for novel therapeutic approaches.
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Is it time to reconcile HDL with cardiovascular diseases and beyond? An update on a paradigm shift.
Martinez, LO, Ingueneau, C, Genoux, A
Current opinion in lipidology. 2020;(5):302-304
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[Challenges in Drug Development Targeting Anti-atherosclerotic Proteins].
Okuhira, K
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2020;(2):153-157
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Abstract
Atherosclerosis is a vascular disease responsible for acute heart attacks and stroke, which are leading causes of death not only in industrialized countries but also worldwide, and the number of patients afflicted by this disease has been increasing in Japan. High-density lipoprotein (HDL) is the plasma lipoprotein that carries what is often called your "good cholesterol" through the blood. This good cholesterol moniker is associated with HDL because higher circulating levels of this lipoprotein are associated with a well-known reduction in the risk of arteriosclerosis. Moreover, many protective mechanisms by which HDL could reduce atherosclerosis are described, including reverse cholesterol transport, along with anti-oxidant, anti-inflammatory and anti-thrombosis activities. However, HDL-modulating therapies to lower cardiovascular risk are not yet available. It has recently been proposed that apolipoprotein A-I (apoA-I) binding protein (AIBP) enhances HDL function by accelerating lipid release from cells and reducing associated inflammatory processes. In this context, our research is focused on the function of HDL-related proteins, such as proteins that regulate HDL production (ATP-binding cassette transporters), and HDL-binding proteins. We expect that these studies could eventually help in the development of HDL-related prognostic and therapeutic strategies to reduce the burden of cardiovascular disease in the future.
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High-Density Lipoprotein Cholesterol in Age-Related Ocular Diseases.
Betzler, BK, Rim, TH, Sabanayagam, C, Cheung, CMG, Cheng, CY
Biomolecules. 2020;(4)
Abstract
There is limited understanding of the specific role of high-density lipoprotein cholesterol (HDL-C) in the development of various age-related ocular diseases, despite it being a common measurable biomarker in lipid profiles. This literature review summarizes current knowledge of the role of HDL-C, if any, in pathogenesis and progression of four age-related ocular diseases, namely age-related macular degeneration (AMD), age-related cataract, glaucoma, and diabetic retinopathy (DR), and will primarily discuss epidemiological and genetic evidence.
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Relationship Between HDL Functional Characteristics and Cardiovascular Health and Potential Impact of Dietary Patterns: A Narrative Review.
Bardagjy, AS, Steinberg, FM
Nutrients. 2019;(6)
Abstract
Cardiovascular disease is a leading cause of death around the world. Overall diet quality and dietary behaviors are core contributors to metabolic health. While therapeutic targets have traditionally focused on levels of lipoprotein cholesterol when evaluating cardiovascular risk, current perspectives on high-density lipoprotein (HDL) have shifted to evaluating the functionality of this lipoprotein particle. Effects of diet on cardiovascular health are mediated through multiple pathways, but the impact on HDL composition and function deserves greater attention. Potential areas of investigation involve changes in particle characteristics, distribution, microRNA cargo, and other functional changes such as improvements to cholesterol efflux capacity. Various dietary patterns like the Mediterranean diet and Dietary Approaches to Stop Hypertension (DASH) diet have beneficial effects on cardiovascular health and may prevent cardiovascular events. These healthful dietary patterns tend to be rich in plant-based foods, with cardiovascular benefits likely resulting from synergistic effects of the individual dietary components. The purpose of this review is to summarize current perspectives on selected functions of HDL particles and how various dietary patterns affect cardiovascular health biomarkers, with a focus on HDL functionality.
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Effects of exercise on HDL functionality.
Ruiz-Ramie, JJ, Barber, JL, Sarzynski, MA
Current opinion in lipidology. 2019;(1):16-23
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Abstract
PURPOSE OF REVIEW Low HDL-cholesterol (HDL-C) levels are a strong predictor of cardiovascular disease risk and can be improved with regular exercise. However, raising HDL-C levels pharmacologically has not shown convincing clinical benefits. Thus, research has recently focused on identifying therapies that improve HDL function, with exercise representing such a potential therapy. The purpose of this review is to summarize the effects of exercise interventions on HDL function. RECENT FINDINGS The effects of exercise and lifestyle interventions on the primary atheroprotective functions of HDL are reviewed, namely, cholesterol efflux, antioxidative, and anti-inflammatory properties. Differences in study design, study population, and assays are discussed to aid in the interpretation of the reviewed studies. SUMMARY There is mixed evidence that regular aerobic exercise improves cholesterol efflux capacity, with recent research suggesting an exercise dose threshold needs to be exceeded to produce beneficial effects. There is preliminary evidence that exercise improves the antioxidative and anti-inflammatory properties of HDL. Although exercise represents a potential therapeutic approach to improve HDL function, the heterogeneity and/or lack of findings warrants more and larger studies to determine what HDL function(s) are most responsive to regular exercise and what dose of exercise elicits the greatest improvements in HDL functionality.
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HDL Cholesterol as a Marker of Disease Severity and Prognosis in Patients with Pulmonary Arterial Hypertension.
Jonas, K, Kopeć, G
International journal of molecular sciences. 2019;(14)
Abstract
The impact of high-density lipoprotein (HDL) cholesterol on the development of atherosclerosis and diseases of systemic circulation has been well documented both in experimental and registry studies. Recent discoveries in pulmonary arterial hypertension (PAH) revealed a significant impact of HDL on pulmonary artery vasoreactivity and patients' prognosis. The vasoprotective activity of HDL primarily involves vascular endothelium that also plays a central role in pulmonary arterial hypertension (PAH) pathobiology. However, the exact mechanism in which this lipoprotein fraction exerts its effect in pulmonary circulation is still under investigation. This paper reviews potential vasoprotective mechanisms of HDL in pulmonary circulation and presents current clinical reports on the role of HDL in PAH patients.
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Meta-regression analysis of the effects of dietary cholesterol intake on LDL and HDL cholesterol.
Vincent, MJ, Allen, B, Palacios, OM, Haber, LT, Maki, KC
The American journal of clinical nutrition. 2019;(1):7-16
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Abstract
BACKGROUND Elevated low-density lipoprotein (LDL) cholesterol is a major risk factor for cardiovascular disease. Dietary guidance recommends reducing saturated fatty acid, trans fatty acid, and cholesterol intakes to reduce circulating LDL cholesterol. Cholesterol intake may also affect high-density lipoprotein (HDL)-cholesterol concentrations, but its impact has not been fully quantified. OBJECTIVES The aims of this study were to investigate the dose-response relation between changes in dietary cholesterol intake and changes in lipoprotein-cholesterol markers for cardiovascular disease risk and to provide a reference for clinicians on how changes in dietary cholesterol intake affect circulating cholesterol concentrations, after accounting for intakes of fatty acids. METHODS We used a Bayesian approach to meta-regression analysis, which uses Markov chain Monte Carlo techniques, to assess the relation between the change in dietary cholesterol (adjusted for dietary fatty acids) and changes in LDL and HDL cholesterol based on the use of data from randomized dietary intervention trials. RESULTS Fifty-five studies (2652 subjects) were included in the analysis. The nonlinear Michaelis-Menten (MM) and Hill models best described the data across the full spectrum of dietary cholesterol changes studied (0-1500 mg/d). Mean predicted changes in LDL cholesterol for an increase of 100 mg dietary cholesterol/d were 1.90, 4.46, and 4.58 mg/dL for the linear, nonlinear MM, and Hill models, respectively. CONCLUSIONS The change in dietary cholesterol was positively associated with the change in LDL-cholesterol concentration. The linear and MM models indicate that the change in dietary cholesterol is modestly inversely related to the change in circulating HDL-cholesterol concentrations in men but is positively related in women. The clinical implications of HDL-cholesterol changes associated with dietary cholesterol remain uncertain.
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Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial.
Nicholls, SJ, Lincoff, AM, Bash, D, Ballantyne, CM, Barter, PJ, Davidson, MH, Kastelein, JJP, Koenig, W, McGuire, DK, Mozaffarian, D, et al
Clinical cardiology. 2018;(10):1281-1288
Abstract
It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels.