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Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future

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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 (20 August 2021) | Viewed by 27996

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Special Issue Editors

Dr. Jose Luis Sanchez-Quesada

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Guest Editor

Cardiovascular Biochemistry Group, Biomedical Research Institute IIB Sant Pau, C/Sant Quintí, 77-79, 08041 Barcelona, Spain
Interests: atherosclerosis mechanisms related to lipoprotein metabolism and inflammation; hyperlipemia; diabetes; obesity

Dr. Sonia Benítez González

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Co-Guest Editor

Institut dInvestigació Biomèdica Sant Pau (IIB Sant Pau), Barceona, Spain
Interests: molecular mechanism of disease; Inflammation; lipoproteins; atherosclerosis; stroke
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Special Issue Information

Dear Colleagues,

Despite the success of statin therapy for decreasing the plasma levels of LDL cholesterol, cardiovascular disease and stroke remain major causes of death in developed countries. Even in subjects at high cardiovascular risk that achieve the target triglyceride and cholesterol levels proposed by international societies, cardiovascular and ischemic events still occur. Although novel and highly effective lipid-lowering therapies such as PCSK9 inhibitors have been developed in recent years, there is an urgent need to develop novel therapies to improve the clinical management of the atherothrombotic disease. Recent studies point to alternative therapeutic targets that could not be only addressed to quantitatively decrease lipid levels in blood but also to improve the function and qualitative characteristics of lipoproteins, thereby decreasing the cardiovascular risk.

This Special Issue on “Lipids, Lipoproteins, and Cardiovascular Disease: Clinical Pharmacology Now and in the Future” aims to update the current pharmacological strategies and to present possible new therapeutic targets that have emerged in recent years. We welcome the submission of original research and review articles on novel molecular mechanisms implicated in the development of cardiovascular and atherothrombotic disease, as well as recent advances in drug targets and therapeutic approaches.

Dr. Jose Luis Sanchez-Quesada
Dr. Sonia Benítez González
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

Lipoproteins
Modified lipoproteins
Lipoprotein function
Atherosclerosis
Cardiovascular disease
Atherothrombotic disease
Therapeutic targets

Published Papers (9 papers)

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Research

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12 pages, 863 KiB

Open AccessArticle

Association of the KDIGO Risk Classification with the Prevalence of Heart Failure in Patients with Type 2 Diabetes

by José Antonio Gimeno-Orna, Luis Rodríguez-Padial, Manuel Anguita-Sánchez, Vivencio Barrios, Javier Muñiz and Antonio Pérez

J. Clin. Med. 2021, 10(20), 4634; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10204634 - 09 Oct 2021

Cited by 2 | Viewed by 2319

Abstract

The objectives of this study were to determine the main characteristics associated with the presence of heart failure (HF) in patients with type 2 diabetes (T2DM), and specifically to assess the association of the risk classification proposed by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines with HF. The DIABET-IC study is a multicentre, observational, prospective and analytical study in T2DM patients recruited in Spanish hospitals. This work, which features a cross-sectional design, has been conducted with the data obtained at the inclusion visit. The main dependent variable analysed was the presence of HF. The predictive variables evaluated were the demography, clinic, laboratory testing (including natriuretic peptides) and echocardiography. Patients were classified according to the number of vascular territories with atherosclerotic involvement and the KDIGO risk category. Multivariate logistic regression models were performed to determine the risk posed by the various baseline variables to present HF at the time of study inclusion. The study included 1517 patients from 58 hospitals, with a mean age of 67.3 (standard deviation (SD): 10) years, out of which 33% were women. The mean DM duration was 14 (SD: 11) years. The prevalence of HF was 37%. In a multivariate analysis, the independent predictors of HF were increased age (odds ratio (OR) per 1 year = 1.02; p = 0.006), decreased systolic blood pressure (OR per 1 mmHg = 0.98; p < 0.001), decreased haemoglobin (OR per 1 g/dL = 0.86; p < 0.001), the presence of obstructive sleep apnoea (OR = 1.61; p = 0.006), the absence of hepatic steatosis (OR = 0.59; p = 0.016), the severity of atherosclerotic involvement (OR 1 territory = 1.38 and OR > 1 territory = 2.39; p = 0.02 and p < 0.001 respectively) and the KDIGO risk classification (high-risk OR = 2.46 and very high-risk OR = 3.39; p < 0.001 for both). The KDIGO risk classification is useful to screen for the presence of HF in T2DM patients. Therefore, we believe that it is necessary to carry out a systematic screening for HF in the high- and very high-risk KDIGO categories. Full article

(This article belongs to the Special Issue Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future)

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15 pages, 1559 KiB

Open AccessArticle

Changes in the Composition and Function of Lipoproteins after Bariatric Surgery in Patients with Severe Obesity

by Idoia Genua, Núria Puig, Inka Miñambres, Sonia Benítez, Pedro Gil, Margarida Grau-Agramunt, Andrea Rivas-Urbina, Carme Balagué, Sonia Fernández-Alanin, Álvaro García-Osuna, Antonio Pérez and José Luis Sánchez-Quesada

J. Clin. Med. 2021, 10(8), 1716; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10081716 - 16 Apr 2021

Cited by 8 | Viewed by 2194

Abstract

The effect of bariatric surgery on lipid profile and the qualitative characteristics of lipoproteins was analyzed in morbidly obese subjects. Thirteen obese patients underwent bariatric surgery. Plasma samples were obtained before surgery and at 6 and 12 months after the intervention. Thirteen healthy subjects comprised the control group. Lipid profile, hsCRP, and the composition and functional characteristics of VLDL, LDL, and HDL were assessed. At baseline, plasma from subjects with obesity had more triglycerides, VLDLc, and hsCRP, and less HDLc than the control group. These levels progressively normalized after surgery, although triglyceride and hsCRP levels remained higher than those in the controls. The main differences in lipoprotein composition between the obese subjects and the controls were increased apoE in VLDL, and decreased cholesterol and apoJ and increased apoC-III content in HDL. The pro-/anti-atherogenic properties of LDL and HDL were altered in the subjects with obesity at baseline compared with the controls, presenting smaller LDL particles that are more susceptible to modification and smaller HDL particles with decreased antioxidant capacity. Bariatric surgery normalized the composition of lipoproteins and improved the qualitative characteristics of LDL and HDL. In summary, patients with obesity present multiple alterations in the qualitative properties of lipoproteins compared with healthy subjects. Bariatric surgery reverted most of these alterations. Full article

(This article belongs to the Special Issue Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future)

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Review

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13 pages, 1248 KiB

Open AccessReview

Arterial Stiffness in Type 1 Diabetes: The Case for the Arterial Wall Itself as a Target Organ

by José-Miguel González-Clemente, Albert Cano, Lara Albert, Olga Giménez-Palop, Ana Romero, Eugenio Berlanga, Joan Vendrell and Gemma Llauradó

J. Clin. Med. 2021, 10(16), 3616; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10163616 - 16 Aug 2021

Cited by 8 | Viewed by 2343

Abstract

Arterial stiffness (AS) integrates the cumulative burden of known and unknown cardiovascular risk factors on the elastic wall of large arteries along the lifespan of an individual. As a marker of vascular aging, AS is an independent predictor of cardiovascular events and improves cardiovascular risk prediction when added to the Framingham Risk Score. In addition, AS may affect the microvasculature and promote the development of microvascular complications. Its impact on both the macro- and microvasculature has led to the concept that the arterial wall itself should be considered as a target organ. Here, we review the biological and clinical consequences of AS on the macro- and microvasculature and the measurement of AS in routine clinical practice. We also discuss the pathophysiological mechanisms underpinning AS development using diabetes and, in particular, type 1 diabetes, as a disease model with a high risk of cardiovascular events and microvascular complications that are accelerated by AS. Full article

(This article belongs to the Special Issue Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future)

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19 pages, 1172 KiB

Open AccessReview

Apolipoprotein and LRP1-Based Peptides as New Therapeutic Tools in Atherosclerosis

by Aleyda Benitez Amaro, Angels Solanelles Curco, Eduardo Garcia, Josep Julve, Jose Rives, Sonia Benitez and Vicenta Llorente Cortes

J. Clin. Med. 2021, 10(16), 3571; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10163571 - 13 Aug 2021

Cited by 7 | Viewed by 2413

Abstract

Apolipoprotein (Apo)-based mimetic peptides have been shown to reduce atherosclerosis. Most of the ApoC-II and ApoE mimetics exert anti-atherosclerotic effects by improving lipid profile. ApoC-II mimetics reverse hypertriglyceridemia and ApoE-based peptides such as Ac-hE18A-NH2 reduce cholesterol and triglyceride (TG) levels in humans. Conversely, other classes of ApoE and ApoA-I mimetic peptides and, more recently, ApoJ and LRP1-based peptides, exhibit several anti-atherosclerotic actions in experimental models without influencing lipoprotein profile. These other mimetic peptides display at least one atheroprotective mechanism such as providing LDL stability against mechanical modification or conferring protection against the action of lipolytic enzymes inducing LDL aggregation in the arterial intima. Other anti-atherosclerotic effects exerted by these peptides also include protection against foam cell formation and inflammation, and induction of reverse cholesterol transport. Although the underlying mechanisms of action are still poorly described, the recent findings suggest that these mimetics could confer atheroprotection by favorably influencing lipoprotein function rather than lipoprotein levels. Despite the promising results obtained with peptide mimetics, the assessment of their stability, atheroprotective efficacy and tissue targeted delivery are issues currently under progress. Full article

(This article belongs to the Special Issue Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future)

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16 pages, 320 KiB

Open AccessReview

Do All Integrase Strand Transfer Inhibitors Have the Same Lipid Profile? Review of Randomised Controlled Trials in Naïve and Switch Scenarios in HIV-Infected Patients

by Maria Saumoy, Jose Luís Sanchez-Quesada, Jordi Ordoñez-Llanos and Daniel Podzamczer

J. Clin. Med. 2021, 10(16), 3456; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10163456 - 04 Aug 2021

Cited by 12 | Viewed by 2003

Abstract

In this study, we aim to explore the effects on lipids of integrase strand transfer inhibitors (INSTIs) in naïve and switch randomised controlled trials, and compare them with protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). We reviewed phase 3/4 randomised clinical trials in the Cochrane and PubMed databases that compare an INSTI with a boosted PI, an NNRTI, or another INSTI plus one or two nucleoside/nucleotide reverse transcriptase inhibitors (NtRTIs) in naïve patients and switching strategies in HIV-infected patients. We reported the baseline plasma concentration of total cholesterol (TC), low and high-density lipoprotein cholesterol (LDL-c, HDL-c), triglycerides (TG), and the TC/HDL-c ratio, as well as the change at weeks 48 and 96, when available. In naïve HIV-infected patients, raltegravir (RAL) and dolutegravir (DTG) have a more favourable lipid profile compared with NNRTI and boosted PI. Elvitegravir (EVG/c) has a superior lipid profile compared with efavirenz and is similar to that observed with ritonavir-boosted atazanavir except in TG, which increases less with EVG/c. In naïve patients, RAL, DTG, and bictegravir (BIC) produce a similar, slight increase in lipids. In switching trials, the regimen change based on a boosted PI or efavirenz to RAL, DTG, or BIC is associated with clinically significant decreases in lipids that are minor when the change is executed on EVG/c. No changes were observed in lipids by switching trials between INSTIs. In summary, RAL, DTG, and BIC have superior lipid profiles compared with boosted-PI, efavirenz, and EVG/c, in studies conducted in naïve participants, and they are associated with a clinically significant decrease in lipoproteins by switching studies. Full article

(This article belongs to the Special Issue Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future)

15 pages, 1273 KiB

Open AccessReview

Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies

by Der-Yuan Chen, Tatsuya Sawamura, Richard A. F. Dixon, José Luis Sánchez-Quesada and Chu-Huang Chen

J. Clin. Med. 2021, 10(9), 1992; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10091992 - 06 May 2021

Cited by 6 | Viewed by 2315

Abstract

Atherosclerosis has been linked with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Autoimmune rheumatic diseases (AIRDs) are associated with accelerated atherosclerosis and ASCVD. However, the mechanisms underlying the high ASCVD burden in patients with AIRDs cannot be explained only by conventional risk factors despite disease-specific factors and chronic inflammation. Nevertheless, the normal levels of plasma low-density lipoprotein (LDL) cholesterol observed in most patients with AIRDs do not exclude the possibility of increased LDL atherogenicity. By using anion-exchange chromatography, human LDL can be divided into five increasingly electronegative subfractions, L1 to L5, or into electropositive and electronegative counterparts, LDL (+) and LDL (−). Electronegative L5 and LDL (−) have similar chemical compositions and can induce adverse inflammatory reactions in vascular cells. Notably, the percentage of L5 or LDL (−) in total LDL is increased in normolipidemic patients with AIRDs. Electronegative L5 and LDL (−) are not recognized by the normal LDL receptor but instead signal through the lectin-like oxidized LDL receptor 1 (LOX-1) to activate inflammasomes involving interleukin 1β (IL-1β). Here, we describe the detailed mechanisms of AIRD-related ASCVD mediated by L5 or LDL (−) and discuss the potential targeting of LOX-1 or IL-1β signaling as new therapeutic modalities for these diseases. Full article

(This article belongs to the Special Issue Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future)

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20 pages, 386 KiB

Open AccessReview

Cardiovascular Disease in Type 1 Diabetes Mellitus: Epidemiology and Management of Cardiovascular Risk

by Cristina Colom, Anna Rull, José Luis Sanchez-Quesada and Antonio Pérez

J. Clin. Med. 2021, 10(8), 1798; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10081798 - 20 Apr 2021

Cited by 19 | Viewed by 4358

Abstract

Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes mellitus (T1DM) patients, and cardiovascular risk (CVR) remains high even in T1DM patients with good metabolic control. The underlying mechanisms remain poorly understood and known risk factors seem to operate differently in T1DM and type 2 diabetes mellitus (T2DM) patients. However, evidence of cardiovascular risk assessment and management in T1DM patients often is extrapolated from studies on T2DM patients or the general population. In this review, we examine the existing literature about the prevalence of clinical and subclinical CVD, as well as current knowledge about potential risk factors involved in the development and progression of atherosclerosis in T1DM patients. We also discuss current approaches to the stratification and therapeutic management of CVR in T1DM patients. Chronic hyperglycemia plays an important role, but it is likely that other potential factors are involved in increased atherosclerosis and CVD in T1DM patients. Evidence on the estimation of 10-year and lifetime risk of CVD, as well as the efficiency and age at which current cardiovascular medications should be initiated in young T1DM patients, is very limited and clearly insufficient to establish evidence-based therapeutic approaches to CVD management. Full article

(This article belongs to the Special Issue Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future)

13 pages, 998 KiB

Open AccessReview

Aggregation Susceptibility of Low-Density Lipoproteins—A Novel Modifiable Biomarker of Cardiovascular Risk

by Katariina Öörni and Petri T. Kovanen

J. Clin. Med. 2021, 10(8), 1769; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10081769 - 19 Apr 2021

Cited by 12 | Viewed by 2542

Abstract

Circulating low-density lipoprotein (LDL) particles enter the arterial intima where they bind to the extracellular matrix and become modified by lipases, proteases, and oxidizing enzymes and agents. The modified LDL particles aggregate and fuse into larger matrix-bound lipid droplets and, upon generation of unesterified cholesterol, cholesterol crystals are also formed. Uptake of the aggregated/fused particles and cholesterol crystals by macrophages and smooth muscle cells induces their inflammatory activation and conversion into foam cells. In this review, we summarize the causes and consequences of LDL aggregation and describe the development and applications of an assay capable of determining the susceptibility of isolated LDL particles to aggregate when exposed to human recombinant sphingomyelinase enzyme ex vivo. Significant person-to-person differences in the aggregation susceptibility of LDL particles were observed, and such individual differences largely depended on particle lipid composition. The presence of aggregation-prone LDL in the circulation predicted future cardiovascular events in patients with atherosclerotic cardiovascular disease. We also discuss means capable of reducing LDL particles’ aggregation susceptibility that could potentially inhibit LDL aggregation in the arterial wall. Whether reductions in LDL aggregation susceptibility are associated with attenuated atherogenesis and a reduced risk of atherosclerotic cardiovascular diseases remains to be studied. Full article

(This article belongs to the Special Issue Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future)

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23 pages, 1945 KiB

Open AccessReview

Going “Green” in the Prevention and Management of Atherothrombotic Diseases: The Role of Dietary Polyphenols

by Ana Reis, Sara Rocha and Victor de Freitas

J. Clin. Med. 2021, 10(7), 1490; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10071490 - 03 Apr 2021

Cited by 9 | Viewed by 6062

Abstract

During the 20th century processed and ready-to-eat foods became routinely consumed resulting in a sharp rise of fat, salt, and sugar intake in people’s diets. Currently, the global incidence of obesity, raised blood lipids, hypertension, and diabetes in an increasingly aged population contributes to the rise of atherothrombotic events and cardiovascular diseases (CVD) mortality. Drug-based therapies are valuable strategies to tackle and help manage the socio-economic impact of atherothrombotic disorders though not without adverse side effects. The inclusion of fresh fruits and vegetables rich in flavonoids to human diets, as recommended by WHO offers a valuable nutritional strategy, alternative to drug-based therapies, to be explored in the prevention and management of atherothrombotic diseases at early stages. Though polyphenols are mostly associated to color and taste in foods, food flavonoids are emerging as modulators of cholesterol biosynthesis, appetite and food intake, blood pressure, platelet function, clot formation, and anti-inflammatory signaling, supporting the health-promoting effects of polyphenol-rich diets in mitigating the impact of risk factors in atherothrombotic disorders and CVD events. Here we overview the current knowledge on the effect of polyphenols particularly of flavonoid intake on the atherothrombotic risk factors and discuss the caveats and challenges involved with current experimental cell-based designs. Full article

(This article belongs to the Special Issue Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future)

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