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Cardiovascular Research: From Molecular Mechanisms to Novel 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 2026) | Viewed by 4274

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Special Issue Editors

Dr. Piotr Musiałek

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Guest Editor

Department of Cardiac and Vascular Diseases, Jagiellonian University, Krakow, Poland
Interests: carotid artery revascularization; cardiovascular
Special Issues, Collections and Topics in MDPI journals

Dr. Monika M. Gladka

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Guest Editor

Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
Interests: heart failure; myocardial infarction; cardiac function; cardiovascular medicine
Special Issues, Collections and Topics in MDPI journals

Dr. Lukasz Tekieli

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Guest Editor

John Paul II Hospital, Krakow, Poland
Interests: coronary artery disease; hypertension; heart defects; pulmonary hypertension; heart failure

Special Issue Information

Dear Colleagues,

Advances in molecular medicine have represented a driving force in the development of innovative therapies for cardiovascular diseases. This Special Issue will explore cutting-edge research in cardiac and vascular biology, focusing on both fundamental molecular mechanisms and novel therapeutic strategies.

We welcome original research and review articles covering a broad spectrum of topics related to cardiovascular pathology and diseases, including, but not limited to, the following:

Molecular and cellular mechanisms behind cardiovascular diseases;
Molecular diagnostics and biomarkers;
Mechanistic insights from bench models, organoids, and in vivo studies;
Gene therapy and regenerative medicine;
Innovative pharmacological and non-pharmacological therapies;
Translational studies, preclinical models, and clinical trials.

This Special Issue will provide a broad update on new discoveries and advances in therapies, supporting the transition of molecular research into clinical practice.

We invite contributions from researchers and clinician–scientists working across molecular biology, cardiovascular medicine, bioengineering, and pharmacology.

Dr. Piotr Musiałek
Dr. Monika M. Gladka
Dr. Lukasz Tekieli
Guest Editors

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 250 words) can be sent to the Editorial Office for assessment.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

cardiovascular diseases
cardiovascular repair and regeneration
molecular cardiology
gene and stem cell therapy
drug and gene delivery
advanced imaging
biomarkers
tissue engineering
thrombosis and clotting abnormalities
animal models of human disease

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Published Papers (6 papers)

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Research

Jump to: Review

20 pages, 1625 KB

Open AccessArticle

The Biological Cost of Every Heartbeat: Imaging-Derived Cardiovascular Vulnerability in Infective Endocarditis

by Corina-Ioana Anton, Rareș Constantin Ranetti and Adrian Streinu-Cercel

Int. J. Mol. Sci. 2026, 27(6), 2733; https://doi.org/10.3390/ijms27062733 - 17 Mar 2026

Viewed by 310

Abstract

Biological cardiovascular vulnerability is defined as an imaging-derived construct integrating myocardial functional impairment, coronary microvascular dysfunction, and modeled hemodynamic burden, including global longitudinal strain, coronary flow reserve, and derived vascular indices. To evaluate whether advanced echocardiographic and coronary Doppler imaging parameters identify biological cardiovascular vulnerability associated with the severity and complications of infective endocarditis beyond conventional structural findings. In this retrospective single-center cohort study, we analyzed consecutive patients with definite infective endocarditis who underwent advanced echocardiographic and coronary Doppler imaging. Comprehensive transthoracic and transesophageal echocardiography assessed vegetation characteristics, left ventricular function, global longitudinal strain (GLS), diastolic indices, right ventricular function, and pulmonary artery systolic pressure. Coronary microvascular function was evaluated noninvasively using transthoracic Doppler-derived coronary flow reserve (CFR) of the left anterior descending artery. Associations with disease severity and perivalvular complications were evaluated using multivariable regression analysis. Reduced coronary flow reserve was independently associated with the composite severe infective endocarditis phenotype, as defined by perivalvular complications, severe valvular dysfunction, or endocarditis team-guided urgent surgical indication. Coronary flow reserve correlated inversely with vegetation size (r = −0.39; p = 0.002) and regurgitation severity (r = −0.36; p = 0.004). Notably, the inverse association between coronary flow reserve and vegetation size showed substantial interindividual variability, particularly among patients with similar vegetation dimensions, suggesting heterogeneity in microvascular vulnerability beyond structural lesion burden. Despite relatively preserved mean arterial pressure across age groups, advanced imaging revealed progressive increases in systemic vascular resistance, declining wall shear stress, impaired microvascular flow, and reduced myocardial reserve. Imaging-derived cardiovascular vulnerability profiles frequently diverged from chronological age, highlighting heterogeneity in cardiovascular reserve despite apparently stable conventional hemodynamic parameters. Advanced echocardiographic and coronary Doppler imaging characterize a spectrum of biological cardiovascular vulnerability that is associated with clinically adjudicated severity in infective endocarditis, rather than serving as independent prognostic predictors. Full article

(This article belongs to the Special Issue Cardiovascular Research: From Molecular Mechanisms to Novel Therapies)

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18 pages, 6195 KB

Open AccessArticle

Decoding Fibroblast Diversity Associated with the Postnatal Loss of Cardiac Regenerative Capacity

by Parisa Aghagolzadeh, Vincent Rapp, Mohamed Nemir, Felix Mahfoud, Marijke Brink and Thierry Pedrazzini

Int. J. Mol. Sci. 2026, 27(6), 2709; https://doi.org/10.3390/ijms27062709 - 16 Mar 2026

Viewed by 494

Abstract

The mammalian heart rapidly loses regenerative capacity after birth and responds to myocardial infarction (MI) with scar formation and development of interstitial fibrosis. Cardiac fibroblasts orchestrate extracellular matrix (ECM) remodeling and cell–cell communication during development and injury; however, how fibroblast heterogeneity and fibroblast communication networks differ between regenerative neonatal and non-regenerative adult hearts remains incompletely defined. We performed scRNA-seq analysis on metabolically active CD45⁻/CD31⁻ nonmyocyte cells from the left ventricles of normal neonatal (P3) and adult (P84) mice to probe heterogeneity in a cardiac fibroblast-enriched population. We identified five transcriptionally distinct cardiac fibroblast subclusters (CF0-CF4) demonstrating different distributions across ages, including an adult-enriched immune/complement-associated program (CF0); an ECM structural-associated program present across ages (CF1); and neonatal-enriched contractile/ECM-remodeling (CF2), Wnt-modulating matrix-regulatory (CF3), and proliferative (CF4) programs. Matrisome category scoring revealed age-dependent divergence in ECM programs: neonatal fibroblasts showed higher enrichment of core matrisome components (particularly collagens and proteoglycans), whereas adult fibroblasts were relatively enriched for matrisome-associated categories, including ECM regulators and secreted factors. Ligand–receptor inference using CellChat demonstrated a broad reduction in fibroblast–fibroblast interaction strength and information flow in adult networks, and adult-enriched signaling was dominated by immune/chemotactic pathways. Finally, projection of subcluster marker programs onto an independent bulk RNA-seq dataset of cardiac fibroblasts 3 days after MI revealed that adult injury partially recapitulates neonatal-associated programs, including activation of the contractile/ECM-remodeling program (CF2) and robust induction of a cell-cycle-associated program (CF4), but lacks an additional neonatal-specific injury program associated with the Wnt-modulating subset (CF3), which was weakly induced or absent in adults. This cardiac fibroblast-enriched single-cell study defines age-dependent fibroblast states, ECM specialization, and communication network architecture that distinguish regenerative neonatal from non-regenerative adult hearts. It also provides a framework to interpret divergent stromal responses after MI and to prioritize fibroblast programs for regenerative and anti-fibrotic strategies. Full article

(This article belongs to the Special Issue Cardiovascular Research: From Molecular Mechanisms to Novel Therapies)

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17 pages, 6258 KB

Open AccessArticle

Nppa and Nppb Deficiency Drives Ventricular Hypertrophy and Subendocardial Gene Deregulation in the Mouse Heart

by Alexandra E. Giovou, Otto J. Mulleners, Marie Günthel, Joyce C. K. Man, Bjarke Jensen, Monika M. Gladka and Vincent M. Christoffels

Int. J. Mol. Sci. 2026, 27(5), 2450; https://doi.org/10.3390/ijms27052450 - 6 Mar 2026

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Abstract

The natriuretic peptides A and B, encoded by NPPA and NPPB, respectively, have complementary and redundant functions in cardiovascular homeostasis. To establish their coordinated roles, we analyzed the cardiac phenotype of a mouse line in which the Nppa–Nppb cluster was deleted from the genome. At 8 weeks of age, Nppa–Nppb^−/− mice (HOM) had significantly larger hearts and cardiomyocytic hypertrophy compared to wild-type and heterozygous mice. Electrocardiogram comparisons showed QRS prolongation in HOM mice. Hypertrophy was confirmed by echocardiography, which further indicated preservation of left ventricular systolic function. Bulk-transcriptomic analysis revealed moderate changes in gene expression of the left ventricle. Genes involved in fatty acid metabolism, ion handling and conductivity, including genes marking the ventricular conduction system, were down-regulated. Spatial transcriptomic analysis revealed the greatest changes in gene expression in the subendocardial wall, where the ventricular conduction system is located. Tbx5, the encoding dosage-sensitive T-box transcription factor Tbx5 that is essential for the expression of ventricular conduction system genes and for Nppa and Nppb, was down-regulated in the ventricles of HOM mice, indicating that a positive feedback loop normally maintains Tbx5 expression. We conclude that homozygous Nppa–Nppb deficiency in mice causes cardiac hypertrophy, including a likely perturbation of the ventricular conduction system. Full article

(This article belongs to the Special Issue Cardiovascular Research: From Molecular Mechanisms to Novel Therapies)

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17 pages, 2287 KB

Open AccessArticle

Evaluation of Potential Molecular Targets of the Alkaloid Epiisopiloturine, Involved in Cardioprotective Effects, Using Computational Molecular Docking in an Animal Model of Cardiac Ischemia and Reperfusion

by Francisco Sandro Menezes-Rodrigues, Elisa Andrade Costa, Pedro Ivo De Marqui Moraes, Erisvaldo Amarante de Araújo, Carlos Eduardo Braga Filho, Leiz Maria Costa Véras, Paulo Sérgio de Araujo Sousa, Jefferson Almeida Rocha, Nelson Americo Hossne Junior, Solange Guizilini, Isadora S. Rocco, Walter José Gomes, Afonso Caricati-Neto, Marcelo Pires-Oliveira, Célia Maria Camelo Silva, Almir Gonçalves Wanderley and Fernando Sabia Tallo

Int. J. Mol. Sci. 2025, 26(19), 9488; https://doi.org/10.3390/ijms26199488 - 28 Sep 2025

Cited by 1 | Viewed by 904

Abstract

The most common cause of morbidity and death worldwide is acute myocardial infarction (AMI), which is typified by severe and deadly arrhythmias resulting from cardiac ischemia and reperfusion (CIR). We chose to investigate the possible cardioprotective activity of epiisopiloturine (EPI), an imidazole alkaloid presents in the leaves of Pilocarpus microphyllus, in an animal model of CIR in rats. Control rats were treated with 0.9% saline solution and then subjected to CIR (SS + CIR); they were compared to rats pretreated with either 10 mg/kg (EPI10 + CIR group) or 15 mg/kg EPI (EPI15 + CIR) before CIR. ECG analysis was used to assess the incidence of ventricular arrhythmias (VAs), atrioventricular block (AVB), and lethality (LET) brought on by CIR in these rats. Serum creatine kinase-MB (CK-MB) was assessed using a colorimetric assay. In comparison to the SS + CIR group, animals treated with EPI15 + CIR had lower AVB incidence, which decreased from 85.7% to 21.4%, while LET incidence decreased from 71.4% to 21.4%. In both EPI10 + CIR and EPI15 + CIR groups, serum CK-MB was lower than in SS + CIR positive controls. These findings suggest that administration of EPI (15 mg/kg) before CIR could reduce the incidences of AVB and LET, as well as cardiac injury markers, which suggests that, likely due to its antioxidant effects, EPI may be a promising drug to reduce LET in patients with severe and fatal arrhythmia due to AMI. Full article

(This article belongs to the Special Issue Cardiovascular Research: From Molecular Mechanisms to Novel Therapies)

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Review

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23 pages, 1439 KB

Open AccessReview

CRISPR and the Future of Cardiac Disease Therapy: A New Genetic Frontier

by Sem Sterckel, Imelda Lizeth Chávez Martínez and Verena Schwach

Int. J. Mol. Sci. 2026, 27(8), 3641; https://doi.org/10.3390/ijms27083641 - 19 Apr 2026

Viewed by 171

Abstract

CRISPR technologies are transforming cardiovascular therapy development by creating an increasingly seamless pipeline from potential target discovery to clinical translation. What began as a genome-editing tool has evolved into a versatile platform that enables researchers to precisely interrogate and modulate cardiac biology with tools such as base- and prime-editors, and CRISPR inhibition and activation. In this review, we follow the use of CRISPR across the stages of biomedical research through to bench-to-bedside application. This review begins by addressing how genome-wide and focused CRISPR screens discover developmental regulators, disease drivers, and drug-response pathways, making the first steps in identifying therapeutic targets. We then explore how CRISPR engineering creates progressively more relevant disease model systems to validate mechanisms of disease and test interventions, helping bridge the translational gaps between the lab and the clinic. Finally, we consider how CRISPR technologies are beginning to enter cardiovascular clinical trials, while highlighting the key challenges that still limit this translation. By linking the latest advances of modern CRISPR platforms to the stages of therapeutic development, this review highlights how CRISPR technology is reshaping the pipeline from molecular insight to clinical innovation in cardiac disease. Full article

(This article belongs to the Special Issue Cardiovascular Research: From Molecular Mechanisms to Novel Therapies)

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21 pages, 880 KB

Open AccessReview

Addressing Unmet Needs in Heart Failure with Preserved Ejection Fraction: Multi-Omics Approaches to Therapeutic Discovery

by Taemin Kim, Michael Sheen, Daniel Ryan and Jacob Joseph

Int. J. Mol. Sci. 2026, 27(2), 673; https://doi.org/10.3390/ijms27020673 - 9 Jan 2026

Cited by 1 | Viewed by 1335

Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for about half of heart failure cases and is linked to aging, obesity, diabetes, and multimorbidity, yet disease-modifying therapies remain limited. A major barrier is heterogeneity: HFpEF comprises overlapping inflammatory, fibrotic, cardiometabolic, and hemodynamic/vascular endophenotypes embedded within systemic cardiorenal and cardiohepatic cross-talk, which conventional metrics such as left ventricular ejection fraction (LVEF), natriuretic peptides (NPs), and standard imaging capture incompletely. In this narrative review, we synthesize clinical, mechanistic, and trial data to describe HFpEF endophenotypes and their multi-organ interactions; critically appraise why traditional diagnostic and enrollment strategies contributed to neutral outcomes in landmark trials; and survey emerging cardiovascular multi-omics studies. We then outline an integrative systems-biology framework that applies (i) within-layer analyses and cross-layer integration, (ii) network-based driver nomination and biomarker discovery, and (iii) target nomination to link molecular programs with circulating markers and candidate therapies. Finally, we discuss practical challenges in implementing multi-omics HFpEF research and highlight future directions such as artificial intelligence (AI)-enabled multi-omics integration, cross-organ profiling, and biomarker-guided, endotype-enriched platform trials. Collectively, these advances position HFpEF as a proving ground for precision cardiology, in which therapies are matched to molecularly defined disease programs rather than ejection-fraction cutoffs alone. Full article

(This article belongs to the Special Issue Cardiovascular Research: From Molecular Mechanisms to Novel Therapies)

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