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Dyslipidemia and Cardiovascular Disease: The Dawn of an Era with New Targets and Novel Therapies

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A special issue of Journal of Cardiovascular Development and Disease (ISSN 2308-3425). This special issue belongs to the section "Acquired Cardiovascular Disease".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 24801

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Dr. Fotios Barkas

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1. Department of Internal Medicine, University Hospital of Ioannina, 45110 Ioannina, Greece
2. Department of Hygiene and Epidemiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
Interests: dyslipidemia; hypercholesterolemia; obesity; diabetes; cardiovascular disease; atherosclerosis
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Dear Colleagues,

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of worldwide mortality and dyslipidemia is a major risk factor. Despite the available lipid-lowering therapies, a considerable proportion of patients with dyslipidemias remain undiagnosed or undertreated. Even patients achieving optimal low-density lipoprotein (LDL) cholesterol levels might still develop a major ASCVD event. This residual ASCVD risk might be attributed to the late initiation of lipid-lowering therapies and lacking control of emerging ASCVD risk factors, such as triglyceride-rich lipoproteins, lipoprotein (a), obesity, or inflammation. In this context, the implementation of therapeutic strategies preventing or reducing cumulative exposure to apolipoprotein B cholesterol-containing lipoproteins and other residual ASCVD risk factors, along with the emergence of novel therapies might provide new opportunities to prevent ASCVD.

With this Special Issue, we are pleased to welcome authors to submit original research articles and comprehensive reviews covering current and evolving aspects of dyslipidemias in the setting of ASCVD prevention.

Dr. Fotios Barkas
Guest Editor

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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 Cardiovascular Development and Disease is an international peer-reviewed open access monthly 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 2700 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

dyslipidemia
hypercholesterolemia
cholesterol
lipoprotein (a)
triglycerides
obesity
cardiovascular disease
atherosclerosis

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Published Papers (9 papers)

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Research

Jump to: Review

10 pages, 528 KiB

Open AccessArticle

Effects of Serum Estradiol on Proprotein Convertase Subtilisin/Kexin Type 9 Levels and Lipid Profiles in Women Undergoing In Vitro Fertilization

by Anna Papanikolaou, Georgia Anastasiou, Fotios Barkas, Constantinos Tellis, Konstantinos Zikopoulos and Evangelos Liberopoulos

J. Cardiovasc. Dev. Dis. 2024, 11(1), 25; https://doi.org/10.3390/jcdd11010025 - 15 Jan 2024

Viewed by 2145

Abstract

Background: The mechanisms underlying the impact of estradiol (E2) on low-density lipoprotein cholesterol (LDL-C) levels are not completely understood, although a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) has been proposed. We aimed to investigate the association between levels of E2, PCSK9, and lipid parameters in premenopausal women undergoing in vitro fertilization (IVF). Methods: Healthy women undergoing IVF in the Department of Obstetrics and Gynecology of the University General Hospital of Ioannina were recruited. Their levels of E2, PCSK9, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), LDL-C, and triglycerides (TGs) were measured 10 days after ovarian depression (E2min) and 7 days after ovarian stimulation (E2max). Results: We included 34 consecutive women of median age 38 (interquartile range 26–46) years who underwent a full IVF cycle. As expected, E2 levels increased by 329.6% from E2min to E2max (108 [47–346] to 464 [241–2471] pg/mL, p < 0.05). During the same time, serum PCSK9 levels decreased by 30.8% (245 ± 80 to 170 ± 64 ng/mL, p < 0.05). TC, LDL-C, and TGs decreased by 0.4%, 3.8%, and 2.2%, respectively, while HDL-C levels increased by 5.3% (all p = NS). Conclusions: The rise in endogenous E2 during an IVF cycle was related with a significant decline in serum PCSK9 levels, but no significant change in plasma lipids during a 7-day period. Full article

(This article belongs to the Special Issue Dyslipidemia and Cardiovascular Disease: The Dawn of an Era with New Targets and Novel Therapies)

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12 pages, 17406 KiB

Open AccessArticle

Dissecting the Impact of Vascular Smooth Muscle Cell ABCA1 versus ABCG1 Expression on Cholesterol Efflux and Macrophage-like Cell Transdifferentiation: The Role of SR-BI

by Olanrewaju Oladosu, Ikechukwu C. Esobi, Rhonda R. Powell, Terri Bruce and Alexis Stamatikos

J. Cardiovasc. Dev. Dis. 2023, 10(10), 416; https://doi.org/10.3390/jcdd10100416 - 2 Oct 2023

Cited by 5 | Viewed by 2128

Abstract

Cholesterol-laden macrophages are recognized as a major contributor to atherosclerosis. However, recent evidence indicates that vascular smooth muscle cells (VSMC) that accumulate cholesterol and transdifferentiate into a macrophage-like cell (MLC) phenotype also play a role in atherosclerosis. Therefore, removing cholesterol from MLC may be a potential atheroprotective strategy. The two transporters which remove cholesterol from cells are ABCA1 and ABCG1, as they efflux cholesterol to apoAI and HDL, respectively. In this study, the well-characterized immortalized VSMC line MOVAS cells were edited to generate ABCA1- and ABCG1-knockout (KO) MOVAS cell lines. We cholesterol-loaded ABCA1-KO MOVAS cells, ABCG1-KO MOVAS cells, and wild-type MOVAS cells to convert cells into a MLC phenotype. When we measured apoAI- and HDL-mediated cholesterol efflux in these cells, we observed a drastic decrease in apoAI-mediated cholesterol efflux within ABCA1-KO MOVAS MLC, but HDL-mediated cholesterol efflux was only partially reduced in ABCG1-KO MOVAS cells. Since SR-BI also participates in HDL-mediated cholesterol efflux, we assessed SR-BI protein expression in ABCG1-KO MOVAS MLC and observed SR-BI upregulation, which offered a possible mechanism explaining why HDL-mediated cholesterol efflux remains maintained in ABCG1-KO MOVAS MLC. When we used lentivirus for shRNA-mediated knockdown of SR-BI in ABCG1-KO MOVAS MLC, this decreased HDL-mediated cholesterol efflux when compared to ABCG1-KO MOVAS MLC with unmanipulated SR-BI expression. Taken together, these major findings suggest that SR-BI expression in MLC of a VSMC origin plays a compensatory role in HDL-mediated cholesterol efflux when ABCG1 expression becomes impaired and provides insight on SR-BI demonstrating anti-atherogenic properties within VSMC/MLC. Full article

(This article belongs to the Special Issue Dyslipidemia and Cardiovascular Disease: The Dawn of an Era with New Targets and Novel Therapies)

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9 pages, 921 KiB

Open AccessArticle

Lipid-Lowering Treatment and the Lipid Goals Attainment in Patients with a Very High Cardiovascular Risk

by Anna Lis, Paulina Lis, Weronika Łowicka, Małgorzata Grabarczyk, Michał Wita, Piotr Żarczyński, Małgorzata Żarczyńska and Maciej Haberka

J. Cardiovasc. Dev. Dis. 2023, 10(8), 329; https://doi.org/10.3390/jcdd10080329 - 2 Aug 2023

Cited by 2 | Viewed by 2292

Abstract

Hypercholesterolemia is the main cardiovascular (CV) risk factor with a large body of evidence. Our aim was to assess the achievement of the main therapeutic goal of Low-Density Lipoprotein Cholesterol (LDL-C) in patients with a very high CV risk and a high-dose statin therapy. The study group consisted of 1413 consecutive patients hospitalised at the Upper-Silesian Medical Centre in Katowice due to acute myocardial infarction (AMI) treated with atorvastatin ≥ 40 mg or rosuvastatin ≥ 20 mg. The lipid profile was performed on admission and within 12 months after AMI. The main therapeutic goal was defined as LDL-C < 55 mg%. The study group (n = 1413) included 979 males (69.3%) with arterial hypertension (83.3%), diabetes (33.5%), peripheral artery disease (13.6%) and nicotinism (46.2%). In the study group, only 61 patients (4.3%) were additionally taking ezetimibe. During hospitalisation, the primary LDL-C goal was found in only 186 patients (13.2%). Subsequently, a follow-up lipidogram within 12 months was performed in 652 patients (46%), and the therapeutic goal was achieved in 255 patients (39%). There were 258 (18.26%) patients who died within 12 months after myocardial infarction. The lowest mortality rate was found in the subgroup of patients with LDL-C < 55 mg% during follow-up (11.02%). The primary lipid goal attainment among patients with a high-dose statin and a very high CV risk is low and far from the expected rate. Patients hospitalised for AMI should be given a combination of statin and ezetimibe more frequently. Low LDL-C levels measured at follow-up predict a lower risk of death at 12-month follow-up in a large group of patients. Full article

(This article belongs to the Special Issue Dyslipidemia and Cardiovascular Disease: The Dawn of an Era with New Targets and Novel Therapies)

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9 pages, 747 KiB

Open AccessArticle

Longitudinal Trends in Severe Dyslipidemia in the Czech Population: The Czech MONICA and Czech Post-MONICA Study

by Renata Cífková, Jan Bruthans, Peter Wohlfahrt, Alena Hrubeš Krajčoviechová, Pavel Šulc, Marie Jozífová, Lenka Eremiášová, Jan Pudil, Aleš Linhart, Jiří Widimský, Jr., Jan Filipovský, Otto Mayer, Jr., Rudolf Poledne, Petr Stávek, Věra Lánská and Larysa Strilchuk

J. Cardiovasc. Dev. Dis. 2023, 10(8), 328; https://doi.org/10.3390/jcdd10080328 - 31 Jul 2023

Cited by 1 | Viewed by 1423

Abstract

Background: Severe hypercholesterolemia is associated with an increase in the risk of developing atherosclerotic cardiovascular disease. The aim of this analysis was to assess longitudinal trends in severe dyslipidemia (defined as total cholesterol > 8 mmol/L or LDL-cholesterol > 5 mmol/L) in a representative population sample of the Czech Republic and to analyze the longitudinal trends in the basic characteristics of individuals with severe dyslipidemia. Methods: Seven independent cross-sectional surveys were organized in the Czech Republic to screen for major cardiovascular risk factors (from 1985 to 2015–2018). A total of 20,443 randomly selected individuals aged 25–64 years were examined. Results: The overall prevalence of severe dyslipidemia was 6.6%, with a significant downward trend from the fifth survey onwards (2000/2001). Over the study period of 30+ years, the individuals with severe dyslipidemia became older, increased in BMI, and did not change their smoking habits. Total cholesterol and non-HDL-cholesterol decreased significantly in both sexes throughout the duration of the study. Conclusions: Despite a significant improvement in lipids in the Czech Republic from 1985, substantially contributing to the decline in cardiovascular mortality, the number of individuals with severe dyslipidemia remained high, and in most cases, they were newly detected during our screening examinations and were thus untreated. Full article

(This article belongs to the Special Issue Dyslipidemia and Cardiovascular Disease: The Dawn of an Era with New Targets and Novel Therapies)

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Review

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15 pages, 720 KiB

Open AccessReview

Atherosclerosis Residual Lipid Risk-Overview of Existing and Future Pharmacotherapies

by Muntaser Omari and Mohammad Alkhalil

J. Cardiovasc. Dev. Dis. 2024, 11(4), 126; https://doi.org/10.3390/jcdd11040126 - 21 Apr 2024

Cited by 2 | Viewed by 2027

Abstract

Patients with atherosclerotic disease remain at increased risk of future events despite receiving optimal medical treatment. This residual risk is widely heterogeneous, but lipoprotein particles and their content play a major role in determining future cardiovascular events. Beyond low-density lipoprotein cholesterol (LDL-c), other lipoprotein particles have not demonstrated similar contribution to the progression of atherosclerosis. Statins, ezetimibe, and more recently, proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors and bempedoic acid have confirmed the causal role of LDL-c in the development of atherosclerosis. Data on high-density lipoprotein cholesterol (HDL-c) suggested a possible causal role for atherosclerosis; nonetheless, HDL-c-raising treatments, including cholesteryl-ester transfer protein (CETP) inhibitors and niacin, failed to confirm this relationship. On the other hand, mendelian randomisation revealed that triglycerides are more implicated in the development of atherosclerosis. Although the use of highly purified eicosapentaenoic acid (EPA) was associated with a reduction in the risk of adverse cardiovascular events, this beneficial effect did not correlate with the reduction in triglycerides level and has not been consistent across large phase 3 trials. Moreover, other triglyceride-lowering treatments, such as fibrates, were not associated with a reduction in future cardiovascular risk. Studies assessing agents targeting angiopoietin-like 3 (lipoprotein lipase inhibitor) and apolipoprotein C3 antisense will add further insights into the role of triglycerides in atherosclerosis. Emerging lipid markers such as lipoprotein (a) and cholesterol efflux capacity may have a direct role in the progression of atherosclerosis. Targeting these biomarkers may provide incremental benefits in reducing cardiovascular risk when added to optimal medical treatment. This Review aims to assess available therapies for current lipid biomarkers and provide mechanistic insight into their potential role in reducing future cardiovascular risk. Full article

(This article belongs to the Special Issue Dyslipidemia and Cardiovascular Disease: The Dawn of an Era with New Targets and Novel Therapies)

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14 pages, 619 KiB

Open AccessReview

Neutrophil Extracellular Traps (NETs) and Atherosclerosis: Does Hypolipidemic Treatment Have an Effect?

by Petros Spyridonas Adamidis, Despoina Pantazi, Iraklis C. Moschonas, Evangelos Liberopoulos and Alexandros D. Tselepis

J. Cardiovasc. Dev. Dis. 2024, 11(3), 72; https://doi.org/10.3390/jcdd11030072 - 21 Feb 2024

Cited by 3 | Viewed by 2360

Abstract

Neutrophil extracellular traps (NETs) have attracted much attention recently, beyond elemental host immunity, due to their fundamental implication in a variety of pathologic conditions and widespread impactful diseases. Atherosclerotic cardiovascular disease (ASCVD) is one of them, and a major cause of mortality and disability worldwide. Consequently, years of basic and clinical research were dedicated to shedding light on every possible pathophysiologic mechanism that could be used as an effective prevention and treatment tool to ameliorate its burden. This led to the development of complex and prevention protocols and regimens that are now widely used, with lipid-lowering treatment being the current cornerstone; however, this is not adequate to alleviate the residual cardiovascular risk, which remains prominent. Despite the demonstrated pathogenic role of NETs in the progression and complications of ASCVD, little is known about their potential as a therapeutic target and the effects hypolipidemics exert on them. Full article

(This article belongs to the Special Issue Dyslipidemia and Cardiovascular Disease: The Dawn of an Era with New Targets and Novel Therapies)

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13 pages, 2018 KiB

Open AccessReview

Bempedoic Acid: An Emerging Therapy for Uncontrolled Low-Density Lipoprotein (LDL) Cholesterol

by Akshyaya Pradhan, Monika Bhandari, Pravesh Vishwakarma, Abhishek Singh, Marco Alfonso Perrone and Rishi Sethi

J. Cardiovasc. Dev. Dis. 2023, 10(5), 195; https://doi.org/10.3390/jcdd10050195 - 27 Apr 2023

Cited by 6 | Viewed by 4957

Abstract

Atherosclerotic cardiovascular disease (ASCVD) is a silent epidemic, which is progressing relentlessly across the globe. Developing countries such as India have a high prevalence of dyslipidemia and consequently a huge burden of coronary artery disease (CAD) and ASCVD. Low-density lipoprotein is regarded as the primary culprit in the genesis of ASCVD, and statins are the first line therapy for LDL-C lowering. Statin therapy has unequivocally demonstrated the benefit of lowering LDL-C in patients across the spectrum of CAD and ASCVD. Muscle symptoms and worsening of glycemic homeostasis could be challenges with statin therapy, especially with the use of high doses. A large fraction of patients are also unable to achieve their LDL goals with statins alone in clinical practice. Moreover, LDL-C goals have become aggressive over years, necessitating a combination of lipid lowering therapies. PCSK-9 inhibitors and Inclisiran have emerged as robust and safe lipid-lowering agents, but parenteral administration and high cost precludes their widespread use. Bempedoic acid is a novel lipid-lowering agent working upstream of statins by inhibiting the enzyme ATP citrate lyase (ACL). The drug produces an average LDL lowering of 22–28% in statin-naïve patients and 17–18% when given to preexisting statin users. Because skeletal muscles lack the ACL enzyme, there is minimal risk of muscle-related symptoms. In combination with ezetimibe, the drug synergistically reduced LDL-C by 39%. Moreover, the drug has no adverse effect on glycemic parameters and lowers hsCRP (inflammation) like statin. The series of four randomized CLEAR trials, involving >4000 patients, have shown consistent LDL lowering across the spectrum of ASCVD patients with or without background therapy. The large and only cardiovascular outcome trial of the drug (CLEAR Outcomes) has recently demonstrated a 13% reduction of MACE at 40 months. Rise in levels of uric acid (four times) and acute gout (three times) are more common compared to placebo with the drug, owing to competitive renal transportation by OAT 2. In a nutshell, Bempedoic acid represents a value addition to the inventory of dyslipidemia management. Full article

(This article belongs to the Special Issue Dyslipidemia and Cardiovascular Disease: The Dawn of an Era with New Targets and Novel Therapies)

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20 pages, 1750 KiB

Open AccessReview

The Impact of the Blood Lipids Levels on Arterial Stiffness

by Mirela Baba, Mihaela Maris, Daniela Jianu, Constantin Tudor Luca, Dana Stoian and Ioana Mozos

J. Cardiovasc. Dev. Dis. 2023, 10(3), 127; https://doi.org/10.3390/jcdd10030127 - 16 Mar 2023

Cited by 14 | Viewed by 3505

Abstract

Arterial stiffness is a recognized predictor of cardiovascular morbidity and death. It is an early indicator of arteriosclerosis and is influenced by numerous risk factors and biological processes. The lipid metabolism is crucial and standard blood lipids, non-conventional lipid markers and lipid ratios are associated with arterial stiffness. The objective of this review was to determine which lipid metabolism marker has a greater correlation with vascular aging and arterial stiffness. Triglycerides (TG) are the standard blood lipids that have the strongest associations with arterial stiffness, and are often linked to the early stages of cardiovascular diseases, particularly in patients with low LDL-C levels. Studies often show that lipid ratios perform better overall than any of the individual variables used alone. The relation between arterial stiffness and TG/HDL-C has the strongest evidence. It is the lipid profile of atherogenic dyslipidemia that is found in several chronic cardio-metabolic disorders, and is considered one of the main causes of lipid-dependent residual risk, regardless of LDL-C concentration. Recently, the use of alternative lipid parameters has also been increasing. Both non-HDL and ApoB are very well correlated with arterial stiffness. Remnant cholesterol is also a promising alternative lipid parameter. The findings of this review suggest that the main focus should be on blood lipids and arterial stiffness, especially in individuals with cardio-metabolic disorders and residual cardiovascular risk. Full article

(This article belongs to the Special Issue Dyslipidemia and Cardiovascular Disease: The Dawn of an Era with New Targets and Novel Therapies)

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16 pages, 2042 KiB

Open AccessReview

Lipoprotein(a): Its Association with Calcific Aortic Valve Stenosis, the Emerging RNA-Related Treatments and the Hope for a New Era in “Treating” Aortic Valve Calcification

by Donatos Tsamoulis, Iliana Siountri and Loukianos S. Rallidis

J. Cardiovasc. Dev. Dis. 2023, 10(3), 96; https://doi.org/10.3390/jcdd10030096 - 23 Feb 2023

Cited by 7 | Viewed by 2884

Abstract

The treatment of patients with aortic valve calcification (AVC) and calcific aortic valve stenosis (CAVS) remains challenging as, until today, all non-invasive interventions have proven fruitless in preventing the disease’s onset and progression. Despite the similarities in the pathogenesis of AVC and atherosclerosis, statins failed to show a favorable effect in preventing AVC progression. The recognition of lipoprotein(a) [Lp(a)] as a strong and potentially modifiable risk factor for the development and, perhaps, the progression of AVC and CAVS and the evolution of novel agents leading in a robust Lp(a) reduction, have rekindled hope for a promising future in the treatment of those patients. Lp(a) seems to promote AVC via a ‘three hit’ mechanism including lipid deposition, inflammation and autotaxin transportation. All of these lead to valve interstitial cells transition into osteoblast-like cells and, thus, to parenchymal calcification. Currently available lipid-lowering therapies have shown a neutral or mild effect on Lp(a), which was proven insufficient to contribute to clinical benefits. The short-term safety and the efficacy of the emerging agents in reducing Lp(a) have been proven; nevertheless, their effect on cardiovascular risk is currently under investigation in phase 3 clinical trials. A positive result of these trials will probably be the spark to test the hypothesis of the modification of AVC’s natural history with the novel Lp(a)-lowering agents. Full article

(This article belongs to the Special Issue Dyslipidemia and Cardiovascular Disease: The Dawn of an Era with New Targets and Novel Therapies)

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