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New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (28 February 2025) | Viewed by 14642

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Prof. Dr. Mohsin Saleet Jafri

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Guest Editor

School of Systems Biology and The Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA 22030, USA
Interests: multiscale systems biology; computational biology; bioinformatics; cardiac physiology; immunology; mitochondria; cellular signaling; neuroscience; algorithms; HPC
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Carola Yvette Förster

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Guest Editor

Julius-Maximilians-Universitat Wurzburg, Department of Anesthesia and Critical Care, Wurzburg, Germany
Interests: cerebrovascular biology; cardiovascular biology; brain-heart; brain cancer; neuroinflammation; ischemic brain injury; systems biology and mathematical modeling
Special Issues, Collections and Topics in MDPI journals

Dr. Tarun W. Dasari

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Guest Editor

University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Interests: cardiovascular diseases

Special Issue Information

Dear Colleagues,

Cardiovascular disease is the leading cause of death worldwide. Cardiovascular disease includes heart failure, ischemia, deep vein thrombosis, pulmonary embolism, heart valve disease, pericarditis, rheumatic heart disease, stroke, and other disorders as well as cardiovascular complications in comorbidity to common major disease, eg DM-diabetic cardiomyopathy or AD-cardiac amyloidosis as examples of the most common types. Understanding the molecular and physiological mechanisms is necessary for developing effective therapeutics. This requires both experimental and computational research modalities spanning scales from the molecular level to the organ system level. Hence, insights can be gained through detailed studies at a particular scale and integration studies that span scales. Advances in the treatment of cardiovascular disease require research from basic science and translational research to clinical studies. This is reflected in recent advances in molecular biomarkers that provide both mechanistic insight as well as clinically actionable treatment strategies.

This Special Issue of Biomolecules will highlight new insights into the mechanisms and therapeutics developed to manage cardiovascular disease. Both new research papers and reviews describing the state of the art in the field and important new directions are welcome.

Prof. Dr. Mohsin Saleet Jafri
Prof. Dr. Carola Yvette Förster
Dr. Tarun W. Dasari
Guest Editors

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Keywords

brain heart-axis
heart & stroke
stress-induced cardiomyopathy
cardiovascular disease

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Published Papers (9 papers)

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Research

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10 pages, 1006 KiB

Open AccessArticle

The VEGFA rs2010963 Gene Polymorphism Is a Potential Genetic Risk Factor for Myocardial Infarction in Slovenian Subjects with Type 2 Diabetes Mellitus

by Emin Grbić, Jernej Letonja and Danijel Petrovič

Biomolecules 2024, 14(12), 1584; https://doi.org/10.3390/biom14121584 - 11 Dec 2024

Viewed by 879

Abstract

Coronary artery disease (CAD) is a life-threatening condition caused by the chronic gradual narrowing of the lumen of the blood vessels of the heart by atherosclerotic plaque with a strong genetic component. The aim of our study was to investigate the association between the VEGFA polymorphism rs2010963 and myocardial infarction in patients with type 2 diabetes, as well as the expression of VEGFA. A total of 1589 unrelated Caucasians with T2DM lasting longer than 10 years were divided into two groups: case group subjects with MI (484) and a control group without a history of CAD (1105). A total of 25 endarterectomy sequesters were immunohistochemically stained to assess VEGFA expression. The rs2010963 polymorphism of the VEGFA gene was genotyped using a KBioscience Ltd. competitive allele-specific fluorescence-based PCR (KASPar) assay. The C allele was significantly more common in the case group according to the dominant model of inheritance (CC + CG vs. GG) (OR: 1.32; 95% CI: 1.05–1.66; p = 0.0197). A statistically significantly higher numerical areal density of VEGFA-positive cells was found in subjects with the C allele (CC + CG genotypes) in comparison to the GG genotype (117 ± 35/mm² vs. 58 ± 21/mm²; p < 0.001). To conclude, the rs2010963 polymorphism is a potential genetic risk factor for myocardial infarction in Slovenian patients with T2DM. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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11 pages, 2704 KiB

Open AccessArticle

Impact of Overnight Storage of Human Atrial Myocytes on Intracellular Calcium Homeostasis and Electrophysiological Utility

by Cristina Aceituno, David Revuelta, Verónica Jiménez-Sábado, Antonino Ginel, Cristina E. Molina and Leif Hove-Madsen

Biomolecules 2024, 14(11), 1415; https://doi.org/10.3390/biom14111415 - 7 Nov 2024

Viewed by 847

Abstract

Human atrial myocytes afford an attractive experimental model to investigate mechanisms underlying electrophysiological alterations in cardiovascular disease. However, this model presents limitations, such as the availability of human atrial tissue and a variable yield of myocytes isolation. Therefore, we aimed to determine whether overnight storage can increase the time window where the electrophysiological properties of human atrial myocytes can be determined. To address this issue, human atrial myocytes isolated from patients undergoing cardiac surgery were used for patch-clamp experiments on the day of cell isolation (Day 1) and the following day (Day 2). The shape of the current–voltage (I–V) relationship for the calcium current (I_Ca) depended on the access resistance and the cell capacitance, with large cells (>75 pF) requiring a lower access resistance (<15 MΩ) than small cells (<40 pF) to avoid distortion of the I–V curve. Importantly, overnight storage did not significantly affect (1) the I_Ca amplitude or properties, (2) sarcoplasmic reticulum calcium homeostasis or (3) the frequency-dependency of the beat-to-beat response. In conclusion, overnight storage of isolated human atrial myocytes at 4 °C does not affect essential features of intracellular calcium homeostasis and, therefore, affords a simple protocol to extend the experimental lifetime of human atrial myocytes. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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16 pages, 5047 KiB

Open AccessArticle

Role of Sex and Early Life Stress Experience on Porcine Cardiac and Brain Tissue Expression of the Oxytocin and H₂S Systems

by Franziska Münz, Nadja Abele, Fabian Zink, Eva-Maria Wolfschmitt, Melanie Hogg, Claus Barck, Josef Anetzberger, Andrea Hoffmann, Michael Gröger, Enrico Calzia, Christiane Waller, Peter Radermacher and Tamara Merz

Biomolecules 2024, 14(11), 1385; https://doi.org/10.3390/biom14111385 - 30 Oct 2024

Viewed by 933

Abstract

Early life stress (ELS) significantly increases the risk of chronic cardiovascular diseases and may cause neuroinflammation. This post hoc study, based on the material available from a previous study showing elevated “serum brain injury markers” in male control animals, examines the effect of sex and/or ELS on the cerebral and cardiac expression of the H₂S and oxytocin systems. Following approval by the Regional Council of Tübingen, a randomized controlled study was conducted on 12 sexually mature, uncastrated German Large White swine of both sexes. The control animals were separated from their mothers at 28–35 days, while the ELS group was separated at day 21. At 20–24 weeks, animals underwent anesthesia, ventilation, and surgical instrumentation. An immunohistochemical analysis of oxytocin, its receptor, and the H₂S-producing enzymes cystathionine-β-synthase and cystathionine-γ-lyase was performed on hypothalamic, prefrontal cortex, and myocardial tissue samples. Data are expressed as the % of positive tissue staining, and differences between groups were tested using a two-way ANOVA. The results showed no significant differences in the oxytocin and H₂S systems between groups; however, sex influenced the oxytocin system, and ELS affected the oxytocin and H₂S systems in a sex-specific manner. No immunohistochemical correlate to the elevated “serum brain injury markers” in male controls was identified. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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22 pages, 6439 KiB

Open AccessArticle

Using a Failing Human Ventricular Cardiomyocyte Model to Re-Evaluate Ca²⁺ Cycling, Voltage Dependence, and Spark Characteristics

by Jerome Anthony E. Alvarez, Mohsin Saleet Jafri and Aman Ullah

Biomolecules 2024, 14(11), 1371; https://doi.org/10.3390/biom14111371 - 28 Oct 2024

Cited by 1 | Viewed by 1154

Abstract

Previous studies have observed alterations in excitation–contraction (EC) coupling during end-stage heart failure that include action potential and calcium (Ca²⁺) transient prolongation and a reduction of the Ca²⁺ transient amplitude. Underlying these phenomena are the downregulation of potassium (K⁺) currents, downregulation of the sarcoplasmic reticulum Ca²⁺ ATPase (SERCA), increase Ca²⁺ sensitivity of the ryanodine receptor, and the upregulation of the sodium–calcium (Na⁼-Ca²⁺) exchanger. However, in human heart failure (HF), debate continues about the relative contributions of the changes in calcium handling vs. the changes in the membrane currents. To understand the consequences of the above changes, they are incorporated into a computational human ventricular myocyte HF model that can explore the contributions of the spontaneous Ca²⁺ release from the sarcoplasmic reticulum (SR). The reduction of transient outward K⁺ current (I_to) is the main membrane current contributor to the decrease in RyR2 open probability and L-type calcium channel (LCC) density which emphasizes its importance to phase 1 of the action potential (AP) shape and duration (APD). During current-clamp conditions, RyR2 hyperphosphorylation exhibits the least amount of Ca²⁺ release from the SR into the cytosol and SR Ca²⁺ fractional release during a dynamic slow–rapid–slow (0.5–2.5–0.5 Hz) pacing, but it displays the most abundant and more lasting Ca²⁺ sparks two-fold longer than a normal cell. On the other hand, under voltage-clamp conditions, HF by decreased SERCA and upregulated I_NCX show the least SR Ca²⁺ uptake and EC coupling gain, as compared to HF by hyperphosphorylated RyR2s. Overall, this study demonstrates that the (a) combined effect of SERCA and NCX, and the (b) RyR2 dysfunction, along with the downregulation of the cardiomyocyte’s potassium currents, could substantially contribute to Ca²⁺ mishandling at the spark level that leads to heart failure. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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Review

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25 pages, 6167 KiB

Open AccessReview

Heart Rate Variability, Microvascular Dysfunction, and Inflammation: Exploring the Potential of taVNS in Managing Heart Failure in Type 2 Diabetes Mellitus

by Serge C. Thal, Sergey Shityakov, Ellaine Salvador and Carola Y. Förster

Biomolecules 2025, 15(4), 499; https://doi.org/10.3390/biom15040499 - 29 Mar 2025

Viewed by 420

Abstract

Patients with type 2 diabetes mellitus (T2DM) predominantly experience mortality due to cardiovascular diseases (CVD), particularly in low- and middle-income nations. Among these, heart failure (HF) is the most severe cardiovascular complication in terms of prognosis and management. Despite advancements in individualized glycemic control and cardiovascular risk management, including the development of novel glucose- and lipid-lowering agents, the prevalence of HF in T2DM patients remains persistently high. This indicates that factors beyond hyperglycemia significantly contribute to the heightened risk of HF associated with T2DM. This review examines critical factors influencing CVD risk in T2DM, particularly the roles of reduced heart rate variability (HRV), a marker of autonomic dysfunction, and chronic inflammation, both of which play pivotal roles in HF pathogenesis. Recent evidence highlights the potential of vagus nerve activation to modulate these risk factors, underscoring its capacity to reduce T2DM-related cardiovascular complications. Specifically, we discuss the therapeutic promise of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive intervention to enhance vagal tone, decrease systemic inflammation, and improve cardiovascular outcomes in T2DM. By addressing the interplay among HRV, microvascular disease, and inflammation, this review provides a comprehensive perspective on the potential utility of taVNS in managing HF in T2DM. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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14 pages, 499 KiB

Open AccessReview

A Review on the Etiologies of the Development of Atrial Fibrillation After Cardiac Surgery

by Christos Ballas, Christos S. Katsouras, Christos Tourmousoglou, Konstantinos C. Siaravas, Ioannis Tzourtzos and Christos Alexiou

Biomolecules 2025, 15(3), 374; https://doi.org/10.3390/biom15030374 - 5 Mar 2025

Viewed by 718

Abstract

Postoperative atrial fibrillation (POAF) is the most common arrhythmia following cardiac surgery. This review critically explores the interplay between cardiopulmonary bypass (CPB) and aortic cross-clamping (ACC) times in POAF development. CPB disrupts systemic homeostasis by inducing inflammatory cascades, oxidative stress, and ischemia–reperfusion injury. Prolonged ACC times further exacerbate myocardial ischemia and structural remodeling, with durations exceeding 60–75 min consistently linked to an increased POAF risk. However, variability in outcomes across studies reveals the complex, multifactorial nature of POAF pathogenesis. Patient-specific variables, such as baseline comorbidities and myocardial protection strategies, modulate these risks, emphasizing the need for personalized surgical approaches. Despite advancements in myocardial protection techniques and anti-inflammatory strategies, the incidence of POAF remains persistently high, indicating a gap in translating mechanistic insights into effective interventions. Emerging biomarkers, including microRNAs (e.g., miR-21, miR-483-5p, etc.) and markers of myocardial injury like troponin I, offer potential for enhanced risk stratification and targeted prevention. However, their clinical applicability requires further validation in diverse patient populations. This review underscores the critical need for integrative research that combines clinical, molecular, and procedural variables to elucidate the nuanced interplay of factors driving POAF. Future directions include leveraging advanced intraoperative monitoring tools, refining thresholds for CPB and ACC times, and developing individualized perioperative protocols. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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35 pages, 1935 KiB

Open AccessReview

Vaccination as a Promising Approach in Cardiovascular Risk Mitigation: Are We Ready to Embrace a Vaccine Strategy?

by Georgios Tsioulos, Natalia G. Vallianou, Alexandros Skourtis, Maria Dalamaga, Evangelia Kotsi, Sofia Kargioti, Nikolaos Adamidis, Irene Karampela, Iordanis Mourouzis and Dimitris Kounatidis

Biomolecules 2024, 14(12), 1637; https://doi.org/10.3390/biom14121637 - 20 Dec 2024

Cited by 1 | Viewed by 1385

Abstract

Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and adaptive immune systems play vital roles in its progression, either exacerbating or alleviating disease development. This intricate interplay positions the immune system as a compelling therapeutic target. Consequently, immunomodulatory strategies have gained increasing attention, though none have yet reached widespread clinical adoption. Safety concerns, particularly the suppression of host immune defenses, remain a significant barrier to the clinical application of anti-inflammatory therapies. Recent decades have revealed the significant role of adaptive immune responses to plaque-associated autoantigens in atherogenesis, opening new perspectives for targeted immunological interventions. Preclinical models indicate that vaccines targeting specific atherosclerosis-related autoantigens can slow disease progression while preserving systemic immune function. In this context, numerous experimental studies have advanced the understanding of vaccine development by exploring diverse targeting pathways. Key strategies include passive immunization using naturally occurring immunoglobulin G (IgG) antibodies and active immunization targeting low-density lipoprotein cholesterol (LDL-C) and apolipoproteins, such as apolipoprotein B100 (ApoB100) and apolipoprotein CIII (ApoCIII). Other approaches involve vaccine formulations aimed at proteins that regulate lipoprotein metabolism, including proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and angiopoietin-like protein 3 (ANGPTL3). Furthermore, the literature highlights the potential for developing non-lipid-related vaccines, with key targets including heat shock proteins (HSPs), interleukins (ILs), angiotensin III (Ang III), and a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS-7). However, translating these promising findings into safe and effective clinical therapies presents substantial challenges. This review provides a critical evaluation of current anti-atherosclerotic vaccination strategies, examines their proposed mechanisms of action, and discusses key challenges that need to be overcome to enable clinical translation. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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32 pages, 4480 KiB

Open AccessReview

Circular RNA in Cardiovascular Diseases: Biogenesis, Function and Application

by Shuai Mei, Xiaozhu Ma, Li Zhou, Qidamugai Wuyun, Ziyang Cai, Jiangtao Yan and Hu Ding

Biomolecules 2024, 14(8), 952; https://doi.org/10.3390/biom14080952 - 6 Aug 2024

Cited by 2 | Viewed by 2104

Abstract

Cardiovascular diseases pose a significant public health challenge globally, necessitating the development of effective treatments to mitigate the risk of cardiovascular diseases. Recently, circular RNAs (circRNAs), a novel class of non-coding RNAs, have been recognized for their role in cardiovascular disease. Aberrant expression of circRNAs is closely linked with changes in various cellular and pathophysiological processes within the cardiovascular system, including metabolism, proliferation, stress response, and cell death. Functionally, circRNAs serve multiple roles, such as acting as a microRNA sponge, providing scaffolds for proteins, and participating in protein translation. Owing to their unique properties, circRNAs may represent a promising biomarker for predicting disease progression and a potential target for cardiovascular drug development. This review comprehensively examines the properties, biogenesis, and potential mechanisms of circRNAs, enhancing understanding of their role in the pathophysiological processes impacting cardiovascular disease. Furthermore, the prospective clinical applications of circRNAs in the diagnosis, prognosis, and treatment of cardiovascular disease are addressed. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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15 pages, 1033 KiB

Open AccessEditor’s ChoiceReview

Implications of GLP-1 Receptor Agonist on Thyroid Function: A Literature Review of Its Effects on Thyroid Volume, Risk of Cancer, Functionality and TSH Levels

by Stefania Capuccio, Sabrina Scilletta, Francesca La Rocca, Nicoletta Miano, Maurizio Di Marco, Giosiana Bosco, Francesco Di Giacomo Barbagallo, Roberto Scicali, Salvatore Piro and Antonino Di Pino

Biomolecules 2024, 14(6), 687; https://doi.org/10.3390/biom14060687 - 13 Jun 2024

Cited by 8 | Viewed by 5090

Abstract

The increasing utilization of Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) in managing type 2 diabetes mellitus has raised interest regarding their impact on thyroid function. In fact, while these agents are well known for their efficacy in glycemic control and weight management, their association with thyroid disorders requires clarification due to the complex interplay between thyroid hormones and metabolic pathways. Thyroid dysfunction commonly co-occurs with metabolic conditions such as diabetes and obesity, suggesting a profound interconnection between these systems. This review aims to contribute to a deeper understanding of the interaction between GLP-1 RAs and thyroid dysfunction and to clarify the safety of GLP-1 RAs in diabetic patients with thyroid disorders. By synthesizing existing evidence, this review highlights that, despite various studies exploring this topic, current evidence is inconclusive, with conflicting results. It is important to note that these drugs are relatively recent, and longer-term studies with larger sample sizes are likely needed to draw clearer conclusions. Currently, no existing guidelines provide definitive directions on this clinical issue; however, it is advisable to include thyroid function tests in the routine screening of diabetic patients, particularly those treated with GLP-1 Ras, with the goal of optimizing patient care and management. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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