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Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 February 2025) | Viewed by 19245

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Dr. Cristina Maria Sena

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1. Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000‐548 Coimbra, Portugal
2. Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal
Interests: obesity; diabetes; vascular dysfunction; oxidative stress; therapeutics; prevention
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Special Issue Information

Dear Colleagues,

The last decades have been marked by an increased prevalence of noncommunicable diseases such as cardiovascular disease. In obesity, the major excessive accumulation of fat can lead to the release of many adipokines and pro-inflammatory cytokines. Type 2 diabetes (T2DM) also confers an elevated risk of developing serious complications, including macrovascular (e.g., cardiovascular disease, stroke) and microvascular (e.g., retinopathy, neuropathy, and nephropathy) diseases. Macro- and microvascular complications are major comorbidities that need to be tackled to improve and extend the quality of life of patients.

This Special Issue aims to discuss new insights into oxidative stress and inflammation in the pathophysiology and treatment of cardiovascular diseases. Studies emphasising the strong crosstalk between oxidative stress, inflammation, and CVD, and various approaches to the prevention of redox/inflammatory biological impacts, are welcome. Additionally, we encourage research on major risk factors, the different mechanisms underlying the disease pathophysiology, and the evaluation of the therapeutic efficacy of novel pharmacological approaches in cellular and rodent models of disease as well as in humans, from a translational perspective. In addition, laboratory biomarkers and physiological tests for the evaluation of oxidative stress status and inflammatory processes may be addressed. Differences in oxidative stress and inflammation are related to genetic susceptibility to cardiovascular diseases and the variability in the assessment of CVD risk between individuals; omics technologies for measuring oxidative stress and inflammation are also within the scope of this Special Issue.

Dr. Cristina Maria Sena
Guest Editor

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Keywords

cardiovascular diseases
oxidative stress
inflammation
risk factors
biomarkers
omics technology

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Published Papers (10 papers)

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Research

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22 pages, 6713 KiB

Open AccessArticle

The Presence of Adipose Tissue in Aortic Valves Influences Inflammation and Extracellular Matrix Composition in Chronic Aortic Regurgitation

by Alba Sádaba, Mattie Garaikoetxea, Carolina Tiraplegui, Susana San-Ildefonso-García, Miriam Goñi-Olóriz, Amaya Fernández-Celis, Ernesto Martín-Núñez, Paula Castillo, Virginia Álvarez, Rafael Sádaba, Eva Jover, Adela Navarro and Natalia López-Andrés

Int. J. Mol. Sci. 2025, 26(7), 3128; https://doi.org/10.3390/ijms26073128 - 28 Mar 2025

Viewed by 256

Abstract

Adipose tissue is present in aortic valves (AVs). Valve interstitial cells (VICs) could differentiate into adipogenic lineages. We here characterize whether the presence of adipose tissue in the AV influences inflammation and extracellular matrix (ECM) composition in patients with aortic regurgitation (AR). A total of 144 AVs were analyzed by histological and molecular techniques. We performed discovery studies using Olink Proteomics^® technology in 40 AVs (N = 16 without and N = 24 with adipose tissue). In vitro, human white adipocytes (HWAs) or VICs were cultured with adipogenic media and co-cultured with control VICs. Of Avs, 67% presented white-like adipocytes within the spongiosa. Discovery studies revealed increased levels of inflammatory and ECM molecules in AVs containing adipocytes. Interestingly, the presence of adipocytes was associated with greater AV thickness, higher inflammation, and ECM remodeling, which was characterized by increased proinflammatory molecules, collagen, fibronectin, proteoglycans, and metalloproteinases. AV thickness positively correlated with markers of adipose tissue, inflammation, and ECM. In vitro, adipocyte-like VICs expressed higher levels of adipocyte markers, increased cytokines, fibronectin, decorin, and MMP-13. Analyses of supernatants from co-cultured control VICs with HWA or adipocyte-like VICs showed higher expression of inflammatory mediators, collagen type I, proteoglycans, and metalloproteinases. AVs presenting adipocytes were thicker and exhibited changes characterized by increased inflammation accompanied by aberrant expression of collagen, proteoglycans, and metalloproteinases. VICs could differentiate into adipogenic pathway, affect neighbor VICs, and contribute to inflammation, collagen and proteoglycan accumulation, as well as to metalloproteinases secretion. In summary, the presence of adipose tissue in AV could modify its composition, favoring inflammation and remodeling with an impact on AV thickness. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies)

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10 pages, 1309 KiB

Open AccessArticle

The Impact of Atorvastatin Treatment on the Distribution of Low-Density Lipoprotein Subfractions and the Level of Vitamin D in Patients After Acute Myocardial Infarction: Preliminary Findings

by Grażyna Sygitowicz, Dariusz Sitkiewicz, Karol Wrzosek and Mirosław Dłuźniewski

Int. J. Mol. Sci. 2024, 25(20), 11264; https://doi.org/10.3390/ijms252011264 - 19 Oct 2024

Cited by 1 | Viewed by 1540

Abstract

Clinical trial results indicate that statin therapy aimed at normalising the lipid profile can prevent and reduce the risk of cardiovascular events. Both LDL and HDL consist of several subfractions, with only the smallest and densest subfractions being the most atherogenic. We examine the effect of Atorvastatin treatment not only on basic lipid profile parameters but also atherogenic lipoprotein subfractions and 25(OH)D levels in patients after the first acute myocardial infarction. The study population had not previously received lipid-lowering medications. Serum 25(OH)D concentration was determined by direct competitive immunochemiluminescent assays. Lipoprotein subfractions, including VLDL, IDL-C, IDL-B, and IDL-A, as well as LDL1, LDL2 (large LDL), and LDL3-7 (sdLDL), were measured in serum (Lipoprint^® system). Almost all patients had 25(OH)D deficiency. Atorvastatin primarily reduced strongly atherogenic sdLDL and decreased the less atherogenic large LDL subfractions. A statistically significant reduction in VLDL cholesterol and IDL fractions was also observed. Analysing LDL subfractions provides a more detailed insight into lipid metabolism and enables the identification of patients with a more atherogenic phenotype. LDL subfractions may thus become not only more accurate prognostic biomarkers but also targets for lipid-lowering therapy. Vitamin D deficiency is associated with atherogenic dyslipidaemia, particularly high levels of sdLDL. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies)

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13 pages, 4066 KiB

Open AccessArticle

Propagermanium as a Novel Therapeutic Approach for the Treatment of Endothelial Dysfunction in Type 2 Diabetes

by Lara Azul, Adriana Leandro, Raquel Seiça and Cristina M. Sena

Int. J. Mol. Sci. 2024, 25(15), 8328; https://doi.org/10.3390/ijms25158328 - 30 Jul 2024

Cited by 1 | Viewed by 1269

Abstract

Propagermanium (PG) has immune modulating activity and anti-inflammatory properties. This work aimed to study the therapeutic efficacy of PG on endothelial and perivascular dysfunction associated with type 2 diabetes. Non-obese type 2 diabetic Goto-Kakizaki (GK) rats were divided into four groups: (1) the control group; (2) the group treated with 50 mg/kg PG; (3) the group fed a high-fat diet (GKHFD); and (4) the group of GKHFD treated with 50 mg/kg PG. PG was given orally for 3 months. Several in vivo parameters and endothelial function were studied in aortas with perivascular adipose tissue PVAT (+) or without PVAT (−). We also determined the vascular inflammation and levels of CD36 in PVAT. In diabetic GK rats, PG did not affect the lipid profile or the results of the intraperitoneal glucose tolerance test. Instead, it improved the fasting glucose levels (18%, p < 0.01), insulin resistance (32%, p < 0.05), endothelial function (33 and 25% in aortas mounted with (+) or without PVAT (−), p < 0.05), and restored the anticontractile effect of the perivascular adipose tissue by reducing its inflammation (56%, p < 0.05) and oxidative stress profile (55%, p < 0.05). Due to its anti-inflammatory characteristics, PG likely improved endothelial dysfunction and restored the perivascular adipose tissue’s anticontractile properties. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies)

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17 pages, 2688 KiB

Open AccessArticle

Integrative Bioinformatics–Gene Network Approach Reveals Linkage between Estrogenic Endocrine Disruptors and Vascular Remodeling in Peripheral Arterial Disease

by Vincent Avecilla, Mayur Doke, Madhumita Das, Oscar Alcazar, Sandeep Appunni, Arthur Rech Tondin, Brandon Watts, Venkataraghavan Ramamoorthy, Muni Rubens and Jayanta Kumar Das

Int. J. Mol. Sci. 2024, 25(8), 4502; https://doi.org/10.3390/ijms25084502 - 19 Apr 2024

Cited by 1 | Viewed by 2030

Abstract

Vascular diseases, including peripheral arterial disease (PAD), pulmonary arterial hypertension, and atherosclerosis, significantly impact global health due to their intricate relationship with vascular remodeling. This process, characterized by structural alterations in resistance vessels, is a hallmark of heightened vascular resistance seen in these disorders. The influence of environmental estrogenic endocrine disruptors (EEDs) on the vasculature suggests a potential exacerbation of these alterations. Our study employs an integrative approach, combining data mining with bioinformatics, to unravel the interactions between EEDs and vascular remodeling genes in the context of PAD. We explore the molecular dynamics by which EED exposure may alter vascular function in PAD patients. The investigation highlights the profound effect of EEDs on pivotal genes such as ID3, LY6E, FOS, PTP4A1, NAMPT, GADD45A, PDGF-BB, and NFKB, all of which play significant roles in PAD pathophysiology. The insights gained from our study enhance the understanding of genomic alterations induced by EEDs in vascular remodeling processes. Such knowledge is invaluable for developing strategies to prevent and manage vascular diseases, potentially mitigating the impact of harmful environmental pollutants like EEDs on conditions such as PAD. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies)

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13 pages, 2297 KiB

Open AccessArticle

Assessment of sST2 Behaviors to Evaluate Severity/Clinical Impact of Acute Pulmonary Embolism

by Luigi Petramala, Antonio Concistrè, Francesca Sarlo, Silvia Baroni, Marianna Suppa, Adriana Servello, Francesco Circosta, Gioacchino Galardo, Orietta Gandini, Luca Marino, Giuseppe Cavallaro, Gino Iannucci and Claudio Letizia

Int. J. Mol. Sci. 2023, 24(5), 4591; https://doi.org/10.3390/ijms24054591 - 27 Feb 2023

Cited by 5 | Viewed by 1901

Abstract

Pulmonary embolism (PE) is a potentially life-threatening disorder. Beyond its usefulness in the prognostic stratification of heart failure, sST2 can represent a biomarker with high utility in several acute conditions. Our study was aimed to investigate whether sST2 can be used as a clinical marker of severity and prognostic outcome in acute PE. We enrolled 72 patients with documented PE and 38 healthy subjects; we measured the plasma concentrations of sST2 to evaluate the prognostic and severity performance of different levels of sST2 according to its association with the pulmonary embolism severity index (PESI) score and several parameters of respiratory function. PE patients had significantly higher levels of sST2 compared with healthy subjects (87.74 ± 17.1 vs. 17.1 ± 0.4 ng/mL, p < 0.001); we found higher PESI scores and serum lactate values in the group of patients with sST2 > 35 ng/mL compared with patients with sST2 < 35 ng/mL (138.7 ± 14.9 vs. 103.7 ± 15.1 and 2.43 ± 0.69 vs. 1.025 ± 0.05 mmol/L, respectively; p < 0.05). Patients with sST2 > 35 ng/mL showed higher radiological severity of PE compared with patients with sST2 < 35 ng/mL. Moreover, sST2 was the strongest parameter with a discriminative capacity for the development of acute respiratory failure and a PESI score >106 with respect to C reactive protein (CRP), creatinine, d-dimer, and serum lactate. We clearly demonstrated that sST2 significantly increased in PE and that its elevation was associated with disease severity. Therefore, sST2 may be used as a clinical marker in the evaluation of PE severity. However, further studies with larger patient populations are required to confirm these findings. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies)

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Review

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32 pages, 2869 KiB

Open AccessReview

Cardiovascular Biomarkers: Tools for Precision Diagnosis and Prognosis

by Vasudeva Reddy Netala, Tianyu Hou, Yanbo Wang, Zhijun Zhang and Sireesh Kumar Teertam

Int. J. Mol. Sci. 2025, 26(7), 3218; https://doi.org/10.3390/ijms26073218 - 30 Mar 2025

Viewed by 793

Abstract

The present study provides a detailed review of cardiovascular biomarkers critical for the diagnosis, prognosis, and pathophysiology of cardiovascular diseases, the leading cause of global morbidity and mortality. These biomarkers aid in detecting disease onset, progression, and therapeutic responses, providing insights into molecular mechanisms. Enzyme markers like AST, CK-MB, LDH, CA-III, and HBDH are pivotal for detecting myocardial injury during acute events. Protein markers such as CRP, H-FABP, and MPO shed light on inflammation and oxidative stress. Cardiac Troponins, the gold standard for myocardial infarction diagnosis, exhibit high specificity and sensitivity, while IMA and GPBB indicate ischemia and early myocardial damage. Peptide markers, including BNP and NT-proBNP, are crucial for heart failure diagnosis and management, reflecting ventricular stress and remodeling. Novel peptides like MR-proANP and MR-proADM aid in assessing disease severity. Lipid markers such as lipoprotein-associated phospholipase A2 and oxylipins provide insights into lipid metabolism and atherosclerosis. Inflammatory and stress-related biomarkers, including TNFα, IL-6, GDF-15, and Pentraxin 3, illuminate chronic inflammation in CVDs. Hormonal markers like copeptin and endothelin-1 highlight neurohormonal activation, while emerging markers such as ST2, galectin-3, PAPP-A, and TMAO elucidate fibrosis, remodeling, and metabolic dysregulation. The inclusion of microRNAs and long non-coding RNAs represents a breakthrough in biomarker research, offering sensitive tools for early detection, risk stratification, and therapeutic targeting. This review emphasizes the diagnostic and prognostic utility of these biomarkers, advancing cardiovascular care through personalized medicine. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies)

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19 pages, 857 KiB

Open AccessReview

Heart Failure and Arrhythmias: Circadian and Epigenetic Interplay in Myocardial Electrophysiology

by Chen Zhu, Shuang Li and Henggui Zhang

Int. J. Mol. Sci. 2025, 26(6), 2728; https://doi.org/10.3390/ijms26062728 - 18 Mar 2025

Viewed by 545

Abstract

Emerging evidence underscores the impact of circadian rhythms on cardiovascular processes, particularly in conditions such as hypertension, myocardial infarction, and heart failure, where circadian rhythm disruptions are linked to disease progression and adverse clinical outcomes. Circadian clock proteins are intricately linked to myocardial electrophysiological remodeling and epigenetic pathways associated with arrhythmias in heart failure. In the context of heart failure, circadian clock dysregulation leads to electrophysiological remodeling in the cardiomyocytes, which can precipitate life-threatening arrhythmias such as ventricular tachycardia (VT) and ventricular fibrillation (VF). This dysregulation may be influenced by environmental factors, such as diet and exercise, as well as genetic factors. Moreover, epigenetic modifications in heart failure have been implicated in the regulation of genes involved in cardiac hypertrophy, fibrosis, and inflammation. The interplay between circadian clock proteins, myocardial electrophysiological remodeling, and epigenetic pathways in heart failure-related arrhythmias is complex and multifaceted. Further research is needed to elucidate how these processes interact and contribute to the development of arrhythmias in heart failure patients. This review aims to explore the connections between circadian rhythms, myocardial electrophysiology, and arrhythmias related to heart failure, with the goal of identifying potential therapeutic targets and interventions that may counteract the adverse effects of circadian disruptions on cardiovascular health. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies)

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15 pages, 840 KiB

Open AccessReview

The Protective Role of Molecular Hydrogen in Ischemia/Reperfusion Injury

by Branislav Kura and Jan Slezak

Int. J. Mol. Sci. 2024, 25(14), 7884; https://doi.org/10.3390/ijms25147884 - 18 Jul 2024

Cited by 8 | Viewed by 2877

Abstract

Ischemia/reperfusion injury (IRI) represents a significant contributor to morbidity and mortality associated with various clinical conditions, including acute coronary syndrome, stroke, and organ transplantation. During ischemia, a profound hypoxic insult develops, resulting in cellular dysfunction and tissue damage. Paradoxically, reperfusion can exacerbate this injury through the generation of reactive oxygen species and the induction of inflammatory cascades. The extensive clinical sequelae of IRI necessitate the development of therapeutic strategies to mitigate its deleterious effects. This has become a cornerstone of ongoing research efforts in both basic and translational science. This review examines the use of molecular hydrogen for IRI in different organs and explores the underlying mechanisms of its action. Molecular hydrogen is a selective antioxidant with anti-inflammatory, cytoprotective, and signal-modulatory properties. It has been shown to be effective at mitigating IRI in different models, including heart failure, cerebral stroke, transplantation, and surgical interventions. Hydrogen reduces IRI via different mechanisms, like the suppression of oxidative stress and inflammation, the enhancement of ATP production, decreasing calcium overload, regulating cell death, etc. Further research is still needed to integrate the use of molecular hydrogen into clinical practice. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies)

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17 pages, 3098 KiB

Open AccessReview

The Role of Circular RNA for Early Diagnosis and Improved Management of Patients with Cardiovascular Diseases

by Claudia Alexandrina Goina, Daniela Marcela Goina, Simona Sorina Farcas and Nicoleta Ioana Andreescu

Int. J. Mol. Sci. 2024, 25(5), 2986; https://doi.org/10.3390/ijms25052986 - 4 Mar 2024

Cited by 5 | Viewed by 3471

Abstract

Cardiovascular diseases (CVDs) are responsible for approximately 17.9 million deaths every year. There is growing evidence that circular RNAs (circRNAs) may play a significant role in the early diagnosis and treatment of cardiovascular diseases. As regulatory molecules, circular RNAs regulate gene expression, interact with proteins and miRNAs, and are translated into proteins that play a key role in a wide variety of biological processes, including the division and proliferation of cells, as well as the growth and development of individuals. An overview of the properties, expression profiles, classification, and functions of circRNAs is presented here, along with an explanation of their implications in cardiovascular diseases including heart failure, hypertension, ischemia/reperfusion injury, myocardial infarction, cardiomyopathies, atherosclerosis, and arrhythmia. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies)

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25 pages, 2327 KiB

Open AccessReview

Unraveling the Intricate Roles of Exosomes in Cardiovascular Diseases: A Comprehensive Review of Physiological Significance and Pathological Implications

by Shuai Zhang, Yu Yang, Xinchen Lv, Wendong Liu, Shaohua Zhu, Ying Wang and Hongfei Xu

Int. J. Mol. Sci. 2023, 24(21), 15677; https://doi.org/10.3390/ijms242115677 - 27 Oct 2023

Cited by 11 | Viewed by 3434

Abstract

Exosomes, as potent intercellular communication tools, have garnered significant attention due to their unique cargo-carrying capabilities, which enable them to influence diverse physiological and pathological functions. Extensive research has illuminated the biogenesis, secretion, and functions of exosomes. These vesicles are secreted by cells in different states, exerting either protective or harmful biological functions. Emerging evidence highlights their role in cardiovascular disease (CVD) by mediating comprehensive interactions among diverse cell types. This review delves into the significant impacts of exosomes on CVD under stress and disease conditions, including coronary artery disease (CAD), myocardial infarction, heart failure, and other cardiomyopathies. Focusing on the cellular signaling and mechanisms, we explore how exosomes mediate multifaceted interactions, particularly contributing to endothelial dysfunction, oxidative stress, and apoptosis in CVD pathogenesis. Additionally, exosomes show great promise as biomarkers, reflecting differential expressions of NcRNAs (miRNAs, lncRNAs, and circRNAs), and as therapeutic carriers for targeted CVD treatment. However, the specific regulatory mechanisms governing exosomes in CVD remain incomplete, necessitating further exploration of their characteristics and roles in various CVD-related contexts. This comprehensive review aims to provide novel insights into the biological implications of exosomes in CVD and offer innovative perspectives on the diagnosis and treatment of CVD. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms, Biomarkers, and Therapies)

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