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Developing Novel Therapies to Prevent Atherosclerosis

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Vascular Medicine".

Deadline for manuscript submissions: closed (5 June 2019) | Viewed by 45941

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Special Issue Editor

Dr. Christina Bursill

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Guest Editor

South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia
Interests: atherosclerosis; inflammation; macrophages; chemokines; high-density lipoproteins; angiogenesis; diabetes

Special Issue Information

Dear Colleagues,

Despite the vast amount of clinical and pre-clinical research that has been invested in the prevention of atherosclerosis, it continues to affect more than 30% of Western populations. The identification of new targets that regulate atherosclerosis, and the development of more plaque modifying therapies, are therefore required. The mechanisms that underlie atherosclerosis are still not fully understood, in particular, how these mechanisms may change with the stage of atherosclerosis is under appreciated. This Special Issue seeks original research manuscripts and reviews that address a range of topics that are related to the use of current therapies, their failures and/or successes, and new up and-and coming therapies. The identification of new regulators of atherosclerosis based on preclinical findings is also welcomed.

Dr. Christina Bursill
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

New mechanisms of atherosclerosis
Plaque inflammation
Anti-inflammatory therapies
Plaque-modifying therapies
Macrophage regulation
Lipoprotein regulation

Published Papers (7 papers)

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Research

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10 pages, 936 KiB

Open AccessArticle

Plasma Aldosterone Concentration as a Determinant for Statin Use among Middle-Aged Hypertensive Patients for Atherosclerotic Cardiovascular Disease

by Jui-Hsiang Lin, Yu-Feng Lin, Wei-Jie Wang, Yuh-Feng Lin, Shih-Chieh Jeff Chueh, Vin-Cent Wu, Tzong-Shinn Chu, Kwan-Dun Wu and On behalf of the Taiwan Primary Aldosteronism Investigation (TAIPAI) Study Group

J. Clin. Med. 2018, 7(11), 382; https://doi.org/10.3390/jcm7110382 - 24 Oct 2018

Cited by 3 | Viewed by 2655

Abstract

The use of statin therapy on the prevention of atherosclerotic cardiovascular disease (ASCVD) is recommended by the American College of Cardiology (ACC) and the American Heart Association (AHA); nevertheless, its validation on primary aldosteronism (PA) patients has not been reported. We investigated the risk of incident ASCVD in middle-aged patients with PA compared with essential hypertension (EH) based on ACC/AHA recommendations. We enrolled 461 PA patients and 553 EH patients. Even though the ratio of metabolic syndrome in each group was similar, the PA group had higher systolic blood pressures, higher low-density lipoprotein levels, higher plasma aldosterone concentration (PAC), lower high-density lipoprotein levels, and higher 10-year ASCVD compared to the EH group. The discriminative power for predicting ASCVD by the recommended statin use from the ACC/AHA guidelines was proper in the PA group (i.e., under the receiver operating characteristic curve (95% confidence interval; 0.94 (0.91–0.96)). The generalized additive model showed patients with PAC higher than 60 ng/dL accompanying the standard timing of the statin use suggested by the ACC/AHA. The ACC/AHA guidelines have good discriminative power in the prediction of middle-aged high-risk hypertensive patients, while PAC identifies those high-risk individuals who may benefit from early statin therapy. Full article

(This article belongs to the Special Issue Developing Novel Therapies to Prevent Atherosclerosis)

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12 pages, 1114 KiB

Open AccessArticle

Pre-Procedural Statin Use Is Associated with Improved Long-Term Survival and Reduced Major Cardiovascular Events in Patients Undergoing Carotid Artery Stenting: A Retrospective Study

by GianLuca Colussi, Francesca Zuttion, Bruno Bais, Pierluigi Dolso, Mariarosaria Valente, Gian Luigi Gigli, Daniele Gasparini, Massimo Sponza, Cristiana Catena, Leonardo A. Sechi and Alessandro Cavarape

J. Clin. Med. 2018, 7(9), 286; https://doi.org/10.3390/jcm7090286 - 17 Sep 2018

Cited by 8 | Viewed by 3243

Abstract

Carotid artery stenting (CAS) is a minimal invasive procedure used to resolve carotid occlusion that can be affected by peri-procedural complications. Statin use before CAS has shown to reduce peri-procedural risk and improve survival, though time-dependent cofactors that influence mortality has not been considered. The aim of this study was to evaluate long-term survival of patients who undergo CAS considering new occurred major adverse cardiovascular event (MACE) as time-dependent cofactor. In this study, 171 high cardiovascular risk patients (age 72 ± 8 years, 125 males) were enrolled after CAS procedure and were followed for a median of 8.4 years. Death occurred in 44% of patients with a mean time to death of 69 ± 39 months and MACE in 34% with a mean time of 35 ± 42 months. In patients who used or not statins at baseline, death occurred in 33% and 65%, respectively (p < 0.001). Survival analysis showed that statin use reduced risk of death (hazard ratio HR 0.36, 95% confidence interval CI 0.23–0.58, p < 0.0001). Including MACE as time-dependent variable did not change beneficial effects of statins. Additionally, statin use was associated with a protective effect on MACE (HR 0.48, 95% CI 0.27–0.85, p = 0.012); particularly, the prevalence of stroke was reduced by 59% (p = 0.018). In multivariate analysis, effects of statins were independent of demographic and anthropometric variables, prevalence of cardiovascular risk factors, renal function, antiplatelet use, and MACE occurrence. In conclusion, use of statins before CAS procedure is associated with increased long-term survival and reduced MACE occurrence. This evidence supports the hypothesis that statin use before CAS might be beneficial in high risk patients. Full article

(This article belongs to the Special Issue Developing Novel Therapies to Prevent Atherosclerosis)

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Review

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26 pages, 2204 KiB

Open AccessReview

MicroRNAs as Therapeutic Targets and Clinical Biomarkers in Atherosclerosis

by Emma L. Solly, Catherine G. Dimasi, Christina A. Bursill, Peter J. Psaltis and Joanne T. M. Tan

J. Clin. Med. 2019, 8(12), 2199; https://doi.org/10.3390/jcm8122199 - 13 Dec 2019

Cited by 45 | Viewed by 5249

Abstract

Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Atherosclerosis develops over several decades and is mediated by a complex interplay of cellular mechanisms that drive a chronic inflammatory milieu and cell-to-cell interactions between endothelial cells, smooth muscle cells and macrophages that promote plaque development and progression. While there has been significant therapeutic advancement, there remains a gap where novel therapeutic approaches can complement current therapies to provide a holistic approach for treating atherosclerosis to orchestrate the regulation of complex signalling networks across multiple cell types and different stages of disease progression. MicroRNAs (miRNAs) are emerging as important post-transcriptional regulators of a suite of molecular signalling pathways and pathophysiological cellular effects. Furthermore, circulating miRNAs have emerged as a new class of disease biomarkers to better inform clinical diagnosis and provide new avenues for personalised therapies. This review focusses on recent insights into the potential role of miRNAs both as therapeutic targets in the regulation of the most influential processes that govern atherosclerosis and as clinical biomarkers that may be reflective of disease severity, highlighting the potential theranostic (therapeutic and diagnostic) properties of miRNAs in the management of cardiovascular disease. Full article

(This article belongs to the Special Issue Developing Novel Therapies to Prevent Atherosclerosis)

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23 pages, 7216 KiB

Open AccessReview

Molecular, Population, and Clinical Aspects of Lipoprotein(a): A Bridge Too Far?

by Natalie C. Ward, Karam M. Kostner, David R. Sullivan, Paul Nestel and Gerald F. Watts

J. Clin. Med. 2019, 8(12), 2073; https://doi.org/10.3390/jcm8122073 - 27 Nov 2019

Cited by 12 | Viewed by 4509

Abstract

There is now significant evidence to support an independent causal role for lipoprotein(a) (Lp(a)) as a risk factor for atherosclerotic cardiovascular disease. Plasma Lp(a) concentrations are predominantly determined by genetic factors. However, research into Lp(a) has been hampered by incomplete understanding of its metabolism and proatherogeneic properties and by a lack of suitable animal models. Furthermore, a lack of standardized assays to measure Lp(a) and no universal consensus on optimal plasma levels remain significant obstacles. In addition, there are currently no approved specific therapies that target and lower elevated plasma Lp(a), although there are recent but limited clinical outcome data suggesting benefits of such reduction. Despite this, international guidelines now recognize elevated Lp(a) as a risk enhancing factor for risk reclassification. This review summarises the current literature on Lp(a), including its discovery and recognition as an atherosclerotic cardiovascular disease risk factor, attempts to standardise analytical measurement, interpopulation studies, and emerging therapies for lowering elevated Lp(a) levels. Full article

(This article belongs to the Special Issue Developing Novel Therapies to Prevent Atherosclerosis)

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20 pages, 17059 KiB

Open AccessReview

Inflammation as a Therapeutic Target in Atherosclerosis

by Mau T Nguyen, Sanuja Fernando, Nisha Schwarz, Joanne TM Tan, Christina A Bursill and Peter J Psaltis

J. Clin. Med. 2019, 8(8), 1109; https://doi.org/10.3390/jcm8081109 - 26 Jul 2019

Cited by 121 | Viewed by 16193

Abstract

Atherosclerotic coronary artery disease (CAD) results from build-up of cholesterol-rich plaques in the walls of the coronary arteries and is a leading cause of death. Inflammation is central to atherosclerosis. Uncontrolled inflammation makes coronary plaques “unstable” and vulnerable to rupture or erosion, leading to thrombosis and myocardial infarction (MI). As multiple inflamed plaques often co-exist in the coronary system, patients are at risk of repeated atherothrombotic cardiovascular events after MI, with rates of 10–12% at one year and 18–20% at three years. This is largely because current therapies for CAD, such as lipid-lowering statins, do not adequately control plaque inflammation. New anti-atherosclerotic agents are therefore needed, especially those that better target inflammation. The recent positive results for the anti-interleukin-1-beta (IL-1β) monoclonal antibody, Canakinumab, in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) clinical trial has provided a major stimulant to the field. It highlights that not only is inflammation important from a pathogenic and risk prediction perspective in CAD, but that reducing inflammation can be beneficial. The challenge is now to find the best strategies to achieve this in real-world practice. This review outlines the role that inflammation plays in atherosclerosis and provides an update on anti-inflammatory therapies currently being investigated to target atherosclerosis. Full article

(This article belongs to the Special Issue Developing Novel Therapies to Prevent Atherosclerosis)

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16 pages, 1933 KiB

Open AccessReview

The Future of Lipid-Lowering Therapy

by Willemien van Zwol, Antoine Rimbert and Jan Albert Kuivenhoven

J. Clin. Med. 2019, 8(7), 1085; https://doi.org/10.3390/jcm8071085 - 23 Jul 2019

Cited by 8 | Viewed by 8005

Abstract

The recent introduction of inhibitors of proprotein convertase subtilisin/kexin 9 to lower low-density lipoprotein (LDL) cholesterol on top of statins or as monotherapy is rapidly changing the landscape of treatment of atherosclerotic cardiovascular disease (ASCVD). However, existing lipid-lowering drugs have little impact on lipoprotein(a) (Lp(a)) or plasma triglycerides, two other risk factors for ASCVD. This review summarizes the evidence and the rationale to target Lp(a) and triglycerides and provides an overview of currently tested strategies to lower Lp(a), apolipoprotein C-III and angiopoietin-like protein 3. In addition, it summarizes new findings on the use of omega-3 fatty acids (OM3FA) to fight ASCVD. With the exception of OM3FA supplementation, the promise of the experimental drugs discussed here depends on the long-term safety and efficacy of monoclonal antibodies and/or antisense oligonucleotides Clinical outcome trials will ultimately prove whether these new therapeutic modalities will reduce ASCVD risk. Full article

(This article belongs to the Special Issue Developing Novel Therapies to Prevent Atherosclerosis)

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Graphical abstract

24 pages, 664 KiB

Open AccessReview

Arterial Lymphatics in Atherosclerosis: Old Questions, New Insights, and Remaining Challenges

by Gábor Csányi and Bhupesh Singla

J. Clin. Med. 2019, 8(4), 495; https://doi.org/10.3390/jcm8040495 - 11 Apr 2019

Cited by 24 | Viewed by 5511

Abstract

The lymphatic network is well known for its role in the maintenance of tissue fluid homeostasis, absorption of dietary lipids, trafficking of immune cells, and adaptive immunity. Aberrant lymphatic function has been linked to lymphedema and immune disorders for a long time. Discovery of lymphatic cell markers, novel insights into developmental and postnatal lymphangiogenesis, development of genetic mouse models, and the introduction of new imaging techniques have improved our understanding of lymphatic function in both health and disease, especially in the last decade. Previous studies linked the lymphatic vasculature to atherosclerosis through regulation of immune responses, reverse cholesterol transport, and inflammation. Despite extensive research, many aspects of the lymphatic circulation in atherosclerosis are still unknown and future studies are required to confirm that arterial lymphangiogenesis truly represents a therapeutic target in patients with cardiovascular disease. In this review article, we provide an overview of factors and mechanisms that regulate lymphangiogenesis, summarize recent findings on the role of lymphatics in macrophage reverse cholesterol transport, immune cell trafficking and pathogenesis of atherosclerosis, and present an overview of pharmacological and genetic strategies to modulate lymphatic vessel density in cardiovascular tissue. Full article

(This article belongs to the Special Issue Developing Novel Therapies to Prevent Atherosclerosis)

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